Novel compounds and pharmaceutical compositions thereof for the treatment of inflammatory disorders

ABSTRACT

The present invention discloses compounds according to Formula I: 
     
       
         
         
             
             
         
       
     
     Wherein R 1a , R 1b , R 2 , R 4 , R 5 , R 6a , R 6b , R 7 , R 8 , W, X, Cy, and the subscript a are as defined herein. The present invention relates to compounds inhibiting autotaxin (NPP2 or ENPP2), methods for their production, pharmaceutical compositions comprising the same, and methods of treatment using the same, for the prophylaxis and/or treatment of diseases involving fibrotic diseases, proliferative diseases, inflammatory diseases, autoimmune diseases, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, dermatological disorders, and/or abnormal angiogenesis associated diseases by administering the compound of the invention.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/572,870, filed on Dec. 17, 2014, which is a continuation of U.S.patent application Ser. No. 14/205,885, filed on Mar. 12, 2014, andclaims priority to U.S. Provisional Application No. 61/781,174, filed onMar. 14, 2013. The entire contents of each of the prior applications arehereby incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to compounds that are inhibitors ofautotaxin, also known as ectonucleotidepyrophosphatase/phosphodiesterase 2 (NPP2 or ENPP2), that is involved infibrotic diseases, proliferative diseases, inflammatory diseases,autoimmune diseases, respiratory diseases, cardiovascular diseases,neurodegenerative diseases, dermatological disorders, and/or abnormalangiogenesis associated diseases. The present invention also providesmethods for the production of a compound of the invention,pharmaceutical compositions comprising a compound of the invention,methods for the prophylaxis and/or treatment of diseases involvingfibrotic diseases, proliferative diseases, inflammatory diseases,autoimmune diseases, respiratory diseases, cardiovascular diseases,neurodegenerative diseases, dermatological disorders, and/or abnormalangiogenesis associated diseases by administering a compound of theinvention.

BACKGROUND OF THE INVENTION

Autotaxin (ATX; also known as ENPP2 (ectonucleotidepyrophosphatase/phosphodiesterase 2) or lysophospholipase D) is a ˜120kDa protein that belongs to the ENPP family of enzymes which is composedof seven members, out of which ENPP1 and ENPP3 are the closest to ATX.Whereas ENPP1 and ENPP3 are active in converting ATP into pyrophosphate(a regulator of mineralization and calcification processes in bone), ATXis the only ENPP enzyme with lysophospholipase D (lysoPLD) activity andis responsible for the hydrolysis of lysophosphatidylcholine (LPC) toproduce the bioactive lipid lysophosphatidic acid (LPA). Several piecesof evidence have established ATX as the main source of LPA in blood. Forexample, blood LPA and ATX levels have been shown to be stronglycorrelated in humans. In addition, LPA levels are reduced by 50% in micecarrying a heterozygous null mutation of ATX (Tanaka, et al., 2006).

Due to the importance of LPA as a biological mediator, the levels ofbio-active LPA are expected to be strictly spatially and temporallycontrolled. The relatively short half life of circulating LPA (˜3 min)in mice is in line with this expectation. In the circulation, where LPClevels are very high (100-200 μM, mainly albumin-bound), ATX isconstitutively active but newly produced LPA is rapidly degraded bymembrane-bound phosphatases and levels of plasma LPA are thereby keptlow (in the low μM range). This is confirmed by the fact that incell-free plasma ex vivo, LPA levels increase at a steady rate. Inaddition, LPA in blood is bound to serum albumin, which might furtherreduce the levels of bio-active LPA. Besides this first level of controlof LPA levels, the spatial control of LPA production is ensured by thecapacity of ATX to bind to cell surface molecules such as integrins andheparan sulphate proteoglycans (HSPs) to facilitate LPA release near toits cognate receptors. Several pieces of evidence support thishypothesis. First, the structural studies of ATX are supporting the factthat the ATX structure is compatible with such a process (Hausmann, J,2011). In addition, several reports indicated how ATX is involved inlymphocyte homing through the interaction with cell surface integrins(Kanda, 2008). It was shown, for example, that ATX can be induced onhigh endothelial venules (HEVs) on sites of inflammation. This ATXexpressed by HEVs acts on HEVs in situ to facilitate lymphocyte bindingto endothelial cells (Nakasaki, et al., 2008). As such, ATX not onlydrives the formation of LPA but, through these cellular interactions,also ensures specificity in LPA signaling.

ATX is widely expressed, with highest mRNA levels detected in brain,lymph nodes, kidney, and testis. Originally discovered as ‘autocrinemotility factor’ in melanoma cells, ATX has emerged as the keyLPA-producing enzyme in plasma and tissues. Unfortunately, embryoniclethality has hampered studies of the importance of ATX in adult life.This embryonic lethality reflects the key role of LPA in variousdevelopmental processes, vasculogenesis in particular. Knock-out studiesof the LPA receptors have been more informative in terms of unravelingthe physiological role of LPA. LPA acts through at least six distinct (Gprotein)-coupled receptors (LPA1-6) found on the surface of differentcell types, three of which belong to the edg receptor family and threeto the non-edg receptor family. LPA interacts with specific Gprotein-coupled receptors (GPCRs), namely LPA1 (also known as EDG2),LPA2 (also known as EDG4), LPA3 (also known as EDG7), LPA4 (also knownas GPR23/p2y9), LPA5 (also known as GPR92/93), LPA6 (also known asp2y5). LPA has also been described to interact with three other GPCRs(GPR87, p2y10, GPR35). In addition, a preference of LPA receptors forspecific LPA species has been demonstrated (Bandoh, et al., 2000). Assuch, the specificity of the LPA activities is controlled by theexpression pattern of the LPA receptors and their downstream signalingroute.

The main part of the LPA responses are mediated through trimericG-proteins and include but are not limited to mitogen-activated proteinkinase (MAPK) activation, adenylyl cyclase (AC) inhibition/activation,phospholipase C (PLC) activation/Ca²⁺ mobilization, arachidonic acidrelease, Akt/PKB activation, and the activation of small GTPases, Rho,ROCK, Rac, and Ras. Other pathways that are affected by LPA receptoractivation include cell division cycle 42/GTP-binding protein (Cdc42),proto-oncogene serine/threonine-protein kinase Raf (c-RAF),proto-oncogene tyrosine-protein kinase Src (c-src), extracellularsignal-regulated kinase (ERK), focal adhesion kinase (FAK), guaninenucleotide exchange factor (GEF), glycogen synthase kinase 3b (GSK3b),c-jun amino-terminal kinase (JNK), MEK, myosin light chain II (MLC II),nuclear factor kB (NF-kB), N-methyl-D-aspartate (NMDA) receptoractivation, phosphatidylinositol3-kinase (PI3K), protein kinase A (PKA),protein kinase C (PKC), and ras-related C3 botulinum toxin substrate 1(RAC1). The actual pathway is influenced by cell type, expression levelof a receptor or signaling protein, receptor usage, and LPAconcentration (Tania, Khan, Zhang, Li, & Song, 2010). LPA has a broadrange of physiological actions and various cellular effects (for exampleblood pressure regulation, platelet activation, smooth musclecontraction, cell growth, cell rounding, neurite retraction, actinstress fiber formation and cell migration). In addition, a preference ofLPA receptors for specific LPA species has been demonstrated (Bandoh, etal., 2000). The knock-out studies for these receptors indicated a rolein bone development (Gennero, et al., 2011), and neurogenesis(Matas-Rico, et al., 2008), embryo implantation (Ye, et al., 2005) andthe formation of blood and lymphatic vessels (Sumida, et al., 2010).

With regard to pathophysiology, a role for LPA and LPA receptors hasbeen claimed in various patho-physiological conditions such asproliferative diseases, neuropathic pain, inflammation, autoimmunediseases, fibrosis, lymphocyte tracking in lymph nodes, obesity,diabetes, or embryonic blood vessel formation.

The role of LPA in lung fibrosis has been well described in literatureand also an involvement in asthma has been claimed. The presentinventors however are the first to report a link to chronic obstructivepulmonary disease (COPD).

Several lines of evidence suggest a role for ATX in the control of lungfunction in disease through effects on lung epithelial cells,fibroblasts and smooth muscle cells. In general, inflammatory conditionsin the lung are often described as associated with increased ATX and LPAlevels. Instillation of LPS in mice, for example, induces increased ATXand LPA levels in the broncho-alveolar lavage (BAL) fluid (Zhao, et al.,2011). Also in humans, a segmental LPS challenge led to increased LPAlevels (Georas, et al., 2007). Overall, the role of LPA in activatinglung epithelial cells, the first line of defense to inhaled noxiousstimuli, towards increased cytokine and chemokine production andmigration have been extensively described (Zhao & Natarajan, 2013).Exogenous LPA promotes inflammatory responses by regulating theexpression of chemokines, cytokines, and cytokine receptors in lungepithelial cells. In addition to the modulation of inflammatoryresponses, LPA regulates cytoskeleton rearrangement and confersprotection against lung injury by enhancing lung epithelial cell barrierintegrity and remodeling.

In the asthmatic individual, the release of normal repair mediators,including LPA, is exaggerated or the actions of the repair mediators areinappropriately prolonged leading to inappropriate airway remodeling.Major structural features of the remodeled airway observed in asthmainclude a thickened lamina reticularis (the basement membrane-likestructure just beneath the airway epithelial cells), increased numbersand activation of myofibroblasts, thickening of the smooth muscle layer,increased numbers of mucus glands and mucus secretions, and alterationsin the connective tissue and capillary bed throughout the airway wall.ATX and/or LPA may contribute to these structural changes in the airway,for example ATX and/or LPA are involved in acute airwayhyperresponsiveness in asthma. The lumen of the remodeled asthmaticairway is narrower due to the thickening of the airway wall, thusdecreasing airflow. Additionally, LPA contributes to the long-termstructural remodeling and the acute hyperresponsiveness of the asthmaticairway, for example LPA contributes to the hyper-responsiveness that isa primary feature of acute exacerbations of asthma. Reports describingthe role of LPA in asthma generated different conclusions, ranging froma protective role (Zhao, et al., 2009) to a negative role (Emo, et al.,2012). The testing of autotaxin inhibitors in models for airway diseasesas described herein allows for the clarification of the potential ofthis enzyme as a drug target.

Fibroblast proliferation and contraction and extracellular matrixsecretion stimulated by LPA contributes to the fibroproliferativefeatures of other airway diseases, such as the peribronchiolar fibrosispresent in chronic bronchitis, and interstitial lung diseases and severeasthma. LPA plays a role in the fibrotic interstitial lung diseases andobliterative bronchiolitis, where both collagen and myofibroblasts areincreased. Studies related to IPF (idiopathic pulmonary fibrosis)indicated an increase in LPA levels in the BAL fluid of patients (Tager,et al., 2008). Further LPA1 knock-out and inhibitor studies revealed akey role for LPA in fibrotic processes in lung and were complemented bystudies using cell-specific knock-out mice lacking ATX in bronchialepithelial cells and macrophages. These mice were shown to be lesssensitive to models of lung fibrosis (Oikonomou, et al., 2012). A rolefor LPA in other fibrotic diseases (kidney and skin) was based onsimilar types of observations (Pradere, et al., 2007), (Castelino, etal., 2011). The role of LPA in lung remodeling relates to the effects ofLPA on both lung fibroblasts (through LPA1) and epithelial cells(through LPA2) (Xu, et al., 2009) have demonstrated that LPA2 plays akey role in the activation of TGFβ in epithelial cells under fibroticconditions. The role of LPA in remodeling and fibrosis is relevant toCOPD, IPF and asthma, diseases in which lung remodeling as a long termoutcome will limit lung function. Finally, of interest towards lungdiseases, in mice, ATX is one of the three main QTLs that appear to beassociated with differences in lung function (Ganguly, et al., 2007).

One prominent area of research interest is the role of ATX-LPA signalingin cancer (Braddock, 2010). Although cancer-specific mutations in ATXhave not been identified so far, overexpression of ATX or individual LPAreceptors in xenografted and transgenic mice promotes tumour formation,angiogenesis and metastasis. Conversely, ATX knockdown in mammarycarcinoma cells reduces their metastatic spread to bone. Several humancancers show elevated ATX and/or aberrant LPA receptor expressionpatterns, as revealed by microarray analyses. Autotaxin is viewed as apro-metastatic enzyme. It has initially been isolated from theconditioned medium of human melanoma cells that stimulates a myriad ofbiological activities, including angiogenesis and the promotion of cellgrowth, migration, survival, and differentiation through the productionof LPA (Lin M. E., 2010). LPA contributes to tumorigenesis by increasingmotility and invasiveness of cells. The initiation, progression andmetastasis of cancer involve several concurrent and sequential processesincluding cell proliferation and growth, survival and anti-apoptosis,migration of cells, penetration of foreign cells into defined tissuesand/or organs, and promotion of angiogenesis.

Therefore, the control of each of these processes by LPA signaling inphysiological and pathophysiological conditions underscores thepotential therapeutic usefulness of modulating LPA signaling pathwaysfor the treatment of cancer. In particular, LPA has been implicated inthe initiation or progression of ovarian cancer, prostate cancer, breastcancer, melanoma, head and neck cancer, bowel cancer (colorectalcancer), thyroid cancer, glioblastoma, follicular lymphoma and othercancers (Gardell, 2006) (Murph, Nguyen, Radhakrishna, & Mills, 2008)(Kishi, 2006).

Furthermore, autotaxin is implicated in the invasive and metastaticprocess of tumor cells, since ectopic overexpression of autotaxin isfrequently observed in malignant tumor tissues such as ovarian cancer(Vidot, et al., 2010), breast cancer (Panupinthu, Lee, & Mills, 2010)(Zhang, et al., 2009), prostate cancer (Nouh, et al., 2009), renalcancer, Hodgkin lymphoma (Baumforth, 2005), hepatocellular carcinoma(Wu, et al., 2010), lung cancer (Xu & Prestwich, 2010), and glioblastoma(Kishi, 2006). Autotaxin overexpression has also been found in a varietyof tumors such as malignant melanoma, teratocarcinoma, neuroblastoma,non-small-cell lung cancer, renal cell carcinoma (Stassar, et al.,2001).

Furthermore, expression of autotaxin by cancer cells controls osteolyticbone metastasis formation. In particular, LPA stimulates directly cancergrowth and metastasis, and osteoclast differentiation. Therefore,targeting the autotaxin/LPA signaling route has also been found to bebeneficial in patients with bone metastases (David, 2010). Finally, theinhibition of autotaxin seems to provide a beneficial adjuvant tochemotherapy for preventing tumor growth and metastasis in patients withhigh autotaxin expression in their tumors (Gaetano, 2009).

Upregulation of the autotaxin-LPA signaling pathway has been observed ina variety of inflammatory conditions. For example, pro-inflammatoryeffects of LPA include degranulation of mast cells, contraction ofsmooth-muscle cells and release of cytokines from dendritic cells. As anindication for its general role in inflammation, LPA and autotaxinactivity have been shown to be induced by carageenan injection into themouse air pouch model, which is used to develop anti-inflammatory drugs,including cyclooxygenase inhibitors for arthritis. Furthermore, areduction in plasma and air pouch LPA has been observed in this rat airpouch model using an autotaxin inhibitor, confirming the role ofautotaxin during inflammation as a major source of LPA (Gierse, 2010).It has been observed that autotaxin inhibitors reduce LPA and PGE2 andalso reduce inflammatory pain.

As another general role in inflammatory diseases, LPA has been shown toinduce chemokinesis in T-cells. Intravenous injection of enzymaticallyinactive autotaxin has been shown to attenuate the homing of T-cells tolymphoid tissues, likely by competing with endogenous autotaxin andexerting a dominant-negative effect. In certain instances, autotaxinfacilitates lymphocyte entry into lymphoid organs (Kanda, 2008).Therefore an autotaxin inhibitor may block lymphocyte migration intosecondary lymphoid organs and be of benefit in autoimmune diseases.

Specifically in rheumatoid arthritis, an increased expression of ATX insynovial fibroblasts from RA patients was demonstrated and ablation ofATX expression in mesenchymal cells (including synovial fibroblasts)resulted in attenuated symptoms in mouse models for rheumatoid arthritis(Nikitopoulou, et al., 2012). As such, the role of autotaxin inrheumatoid arthritis has been strongly established.

Several lines of evidence suggest a role for LPA in vascular injury andatherosclerosis. These relate to the role of LPA in modulatingendothelial barrier function and the phenotype of vascular smooth musclecells and the action of LPA as a weak platelet agonist. Platelets havebeen identified as important participants in LPA production in thecirculation in some settings, mainly by providing sufficient LPCamounts. Plasma autotaxin associates with platelets during aggregationand concentrates in arterial thrombus, and activated but not restingplatelets bind recombinant autotaxin in an integrin-dependent manner.Experimental induction of thrombocytopenia in rats, using ananti-platelet antibody, decreases the production of LPA in serum byalmost 50%, which suggests a role for LPA during clotting. In someinstances, transgenic overexpression of autotaxin elevates circulatingLPA levels and induces a bleeding diathesis and attenuation ofthrombosis in mice. Intravascular administration of exogenous LPArecapitulates the prolonged bleeding time observed in autotaxin-Tg mice.Finally, autotaxin^(+/−) mice, which have ˜50% normal plasma LPA levels,are more prone to thrombosis.

In addition to a role in blood clotting, LPA has multiple effects on theendothelial monolayer permeability increase, and endothelial cells, inparticular in critical aspects of angiogenesis such as cell migrationstimulation and invasion. Furthermore, LPA also exerts migratory andcontractile effects on vascular smooth muscle cells: autotaxin-mediatedLPA production and subsequent LPA signaling contributes to vasculardevelopment by stimulating endothelial cell migration and invasion aswell as regulating adhesive interactions with the extracellular matrixand smooth muscle cells. For example, similar vascular defects have beenobserved in autotaxin-deficient mice and in mice lacking genes involvedin cell migration and adhesion (Van Meeteren, et al., 2006). Thereforean autotaxin inhibitor may have benefit in some diseases involvingdysregulated angiogenesis.

LPA induces neuropathic pain as well as demyelination and pain-relatedprotein expression changes via LPA1 (Inoue, et al., 2008). ATXheterozygous knockout mice show about 50% recovery of nerveinjury-induced neuropathic pain compared to wild type mice.Lysophosphatidylcholine (LPC), also known as lyso-lecithin, is known toinduce neuropathic pain. It has been observed that LPC-inducedneuropathic pain is partially reduced in ATX heterozygous knockout mice.These results support the idea that LPA is produced by autotaxinresulting in neuropathic pain (Lin M. E., 2010).

Autotaxin is also implicated in metabolic diseases, in particularobesity and diabetes (Federico, et al., 2012). In some instances,autotaxin is responsible for the lysoPLD activity released by adipocytesand exerts a paracrine control on preadipocyte growth via anLPA-dependent mechanism. In addition, autotaxin is upregulated duringadipocyte differentiation and in genetic obesity. In certain instances,autotaxin mRNA is upregulated in adipocytes from db/db mice suggestingthat the upregulation of autotaxin is related to the severe type 2diabetes phenotype and adipocyte insuline resistance. In some instances,upregulation of adipocyte autotaxin is associated with type 2 diabetesin human (Ferry, 2003). The relationship between adipocyte and autotaxinbiology suggests the use of an autotaxin inhibitor for the treatment ofmetabolic diseases.

Finally, two other conditions clearly related to autotaxin biology arecholestatic pruritus (Kremer, et al., 2010) and regulation of ocularpressure (Iyer, et al., 2012).

The current therapies are not satisfactory and therefore there remains aneed to identify further compounds that may be of use in the treatmentof fibrotic diseases, proliferative diseases, inflammatory diseases,autoimmune diseases, respiratory diseases, cardiovascular diseases,neurodegenerative diseases, dermatological disorders, and/or abnormalangiogenesis associated diseases. The present invention thereforeprovides compounds, methods for their manufacture and pharmaceuticalcompositions comprising a compound of the invention together with asuitable pharmaceutical carrier. The present invention also provides forthe use of a compound of the invention in the preparation of amedicament for the treatment of fibrotic diseases, proliferativediseases, inflammatory diseases, autoimmune diseases, respiratorydiseases, cardiovascular diseases, neurodegenerative diseases,dermatological disorders, and/or abnormal angiogenesis associateddiseases.

SUMMARY OF THE INVENTION

The present invention is based on the identification of novel compounds,and their ability to act as inhibitors of autotaxin and that they may beuseful for the treatment of fibrotic diseases, proliferative diseases,inflammatory diseases, autoimmune diseases, respiratory diseases,cardiovascular diseases, neurodegenerative diseases, dermatologicaldisorders, and/or abnormal angiogenesis associated diseases. The presentinvention also provides methods for the production of these compounds,pharmaceutical compositions comprising these compounds and methods oftreatment for fibrotic diseases, proliferative diseases, inflammatorydiseases, autoimmune diseases, respiratory diseases, cardiovasculardiseases, neurodegenerative diseases, dermatological disorders, and/orabnormal angiogenesis associated diseases by administering the compoundsof the invention.

Accordingly, in a first aspect of the invention, the compounds of theinvention are provided having a Formula (I):

-   -   wherein    -   R^(1a) is H, halo or C₁₋₄ alkyl;    -   R^(1b) is:        -   halo,        -   C₁₋₄ alkyl (which alkyl is optionally substituted with one            or more independently selected halo), or        -   C₁₋₄ alkoxy (which alkoxy is optionally substituted with one            or more independently selected halo);    -   X is —S—, —O—, —N═CH—, —CH═N— or —CH═CH—;    -   W is N, or CR³    -   when W is N, R² is:        -   H,        -   —CN,        -   halo,        -   C₁₋₄ alkyl (which alkyl is optionally substituted with one            or more independently selected OH, or CN),        -   —C(═O)CH₃,        -   —C(═O)CF₃,        -   —C(═O)OCH₃,        -   —C(═O)NH₂, or        -   —NHC(═O)CH₃, or    -   when W is CR³, one of R² or R³ is:        -   H,        -   —CN,        -   halo,        -   C₁₋₄ alkyl (which alkyl is optionally substituted with one            or more independently selected OH, or CN),        -   —C(═O)CH₃,        -   —C(═O)CF₃,        -   —C(═O)OCH₃,        -   —C(═O)NH₂, or        -   —NHC(═O)CH₃,    -   and the other is H, or C₁₋₄ alkyl;    -   R⁴ is C₁₋₄ alkyl;    -   R⁵ is C₁₋₄ alkyl optionally substituted with one or more        independently selected CN, OH, halo, or —C(═O)NH₂;    -   one of R^(6a) or R^(6b) is selected from H, —CH₃, and halo, and        the other is H;    -   Cy is:        -   C₄₋₁₀ cycloalkyl,        -   4-10 membered mono or bicyclic heterocycloalkyl containing            one or more heteroatoms independently selected from O, N,            and S, or        -   4-7 membered heterocycloalkenyl containing 1 double bond,            containing one or more heteroatoms independently selected            from O, N, and S;    -   each R⁷ is independently selected from:        -   OH,        -   oxo,        -   halo, and        -   C₁₋₄ alkyl (which alkyl is optionally substituted with one            or more independently selected OH, or C₁₋₄ alkoxy);    -   the subscript a is 0, 1 or 2;    -   R⁸ is -(L₁-W₁)_(m)-L₂-G₁,    -   wherein        -   L₁ is absent, or is —O—, —C(═O)—, —NR^(i), —NR^(h)C(═O)—, or            —SO₂—;        -   W₁ is C₁₋₄ alkylene;        -   the subscript m is 0, or 1;        -   L₂ is absent, or is —O—, —C(═O)—, —C(═O)O—, —OC(═O)—,            —C(═O)—C(═O)—, —C(═O)—C(═O)NR^(a)—, —NR^(b)—, —C(═O)NR^(c)—,            —NR^(d)C(═O)—, —NR^(j)C(═O)O—, —SO₂—, —SO₂NR^(e)— or            —NR^(f)SO₂—;        -   G₁ is            -   H,            -   —CN,            -   C₁₋₄ alkyl (which alkyl is optionally substituted with                one or more independently selected —CN, OH, halo or                phenyl),            -   C₃₋₇ cycloalkyl (which cycloalkyl is optionally                substituted with —NH₂),            -   5-6 membered heterocycloalkenyl containing 1 double bond                containing one or more heteroatoms independently                selected from O, N, and S (which heterocycloalkenyl is                optionally substituted with one or more independently                selected R⁹ groups),            -   4-10 membered mono, bi or spirocyclic heterocycloalkyl                containing one or more heteroatoms independently                selected from O, N, and S (which heterocycloalkyl is                optionally substituted with one or more independently                selected R⁹ groups), or            -   5-6 membered heteroaryl containing one or more                heteroatoms independently selected from O, N, and S                (which heteroaryl is optionally substituted with one or                more independently selected R¹⁰ groups),    -   each R⁹ is oxo, or R¹⁰;    -   each R¹⁰ is:        -   —OH,        -   halo,        -   —CN,        -   C₁₋₄ alkyl (which alkyl is optionally substituted with one            or more independently selected OH, halo, or phenyl),        -   C₁₋₄ alkoxy,        -   C₃₋₇ cycloalkyl,        -   phenyl,        -   —SO₂CH₃,        -   —C(═O)C₁₋₄ alkoxy,        -   —C(═O)C₁₋₄ alkyl, or        -   —NR^(g)C(═O)C₁₋₄ alkyl; and    -   each R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), R^(h),        R^(i), and R^(j) is independently selected from H and C₁₋₄        alkyl.

In one aspect, the compounds of the invention are inhibitors ofautotaxin. Furthermore, the compounds of the invention may exhibit lowclearance, possibly resulting in low therapeutic dose levels.

In a more particular aspect, the compounds of the invention are activein vivo against IPF and/or COPD.

In a particular aspect, the compounds of the invention are provided foruse in the prophylaxis and/or treatment of fibrotic diseases,proliferative diseases, inflammatory diseases, autoimmune diseases,respiratory diseases, cardiovascular diseases, neurodegenerativediseases, dermatological disorders, and/or abnormal angiogenesisassociated diseases.

In a further aspect, the present invention provides pharmaceuticalcompositions comprising a compound of the invention, and apharmaceutical carrier, excipient or diluent. In a particular aspect,the pharmaceutical composition may additionally comprise furthertherapeutically active ingredients suitable for use in combination withthe compounds of the invention. In a more particular aspect, the furthertherapeutically active ingredient is an agent for the treatment offibrotic diseases, proliferative diseases, inflammatory diseases,autoimmune diseases, respiratory diseases, cardiovascular diseases,neurodegenerative diseases, dermatological disorders, and/or abnormalangiogenesis associated diseases.

Moreover, the compounds of the invention, useful in the pharmaceuticalcompositions and treatment methods disclosed herein, arepharmaceutically acceptable as prepared and used.

In a further aspect of the invention, this invention provides a methodof treating a mammal, in particular humans, afflicted with a conditionselected from among those listed herein, and particularly fibroticdiseases, proliferative diseases, inflammatory diseases, autoimmunediseases, respiratory diseases, cardiovascular diseases,neurodegenerative diseases, dermatological disorders, and/or abnormalangiogenesis associated diseases, which method comprises administeringan effective amount of the pharmaceutical composition or compounds ofthe invention as described herein.

The present invention also provides pharmaceutical compositionscomprising a compound of the invention, and a suitable pharmaceuticalcarrier, excipient or diluent for use in medicine. In a particularaspect, the pharmaceutical composition is for use in the prophylaxisand/or treatment of fibrotic diseases, proliferative diseases,inflammatory diseases, autoimmune diseases, respiratory diseases,cardiovascular diseases, neurodegenerative diseases, dermatologicaldisorders, and/or abnormal angiogenesis associated diseases.

In additional aspects, this invention provides methods for synthesizingthe compounds of the invention, with representative synthetic protocolsand pathways disclosed later on herein.

Other objects and advantages will become apparent to those skilled inthe art from a consideration of the ensuing detailed description.

It will be appreciated that compounds of the invention may bemetabolized to yield biologically active metabolites.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The following terms are intended to have the meanings presentedtherewith below and are useful in understanding the description andintended scope of the present invention.

When describing the invention, which may include compounds,pharmaceutical compositions containing such compounds and methods ofusing such compounds and compositions, the following terms, if present,have the following meanings unless otherwise indicated. It should alsobe understood that when described herein any of the moieties definedforth below may be substituted with a variety of substituents, and thatthe respective definitions are intended to include such substitutedmoieties within their scope as set out below. Unless otherwise stated,the term ‘substituted’ is to be defined as set out below. It should befurther understood that the terms ‘groups’ and ‘radicals’ can beconsidered interchangeable when used herein.

The articles ‘a’ and ‘an’ may be used herein to refer to one or to morethan one (i.e. at least one) of the grammatical objects of the article.By way of example ‘an analogue’ means one analogue or more than oneanalogue.

As used herein the term ‘LPA’ relates to lysophosphatidic acid which isa member of the membrane-derived bioactive lipid mediators, furthercomprising sphingosine-1-phosphate (S1P), lysophosphatidylcholine (LPC),and sphingosylphosphorylcholine (SPC). LPA interacts with specific Gprotein-coupled receptors (GPCRs), namely LPA₁, LPA₂, LPA₃, LPA₄, LPA₅,LPA₆, LPA₇, LPA₈, in an autocrine and paracrine fashion, to activateintracellular signaling pathways, and in turn produce a variety ofbiological responses.

‘Alkyl’ means straight or branched aliphatic hydrocarbon with the numberof carbon atoms specified. Particular alkyl groups have 1 to 8 carbonatoms. More particular is lower alkyl which has 1 to 6 carbon atoms. Afurther particular group has 1 to 4 carbon atoms. Exemplary straightchained groups include methyl, ethyl n-propyl, and n-butyl. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl, propylor butyl is attached to a linear alkyl chain, exemplary branched chaingroups include isopropyl, iso-butyl, t-butyl and isoamyl.

‘Alkoxy’ refers to the group —OR²⁶ where R²⁶ is alkyl with the number ofcarbon atoms specified. Particular alkoxy groups are methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy,n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are loweralkoxy, i.e. with between 1 and 6 carbon atoms. Further particularalkoxy groups have between 1 and 4 carbon atoms.

‘Alkylene’ refers to divalent alkene radical groups having the number ofcarbon atoms specified, in particular having 1 to 6 carbon atoms andmore particularly 1 to 4 carbon atoms which can be straight-chained orbranched. This term is exemplified by groups such as methylene (—CH₂—),ethylene (—CH₂—CH₂—), or —CH(CH₃)— and the like.

‘Alkenyl’ refers to monovalent olefinically (unsaturated) hydrocarbongroups with the number of carbon atoms specified. Particular alkenyl has2 to 8 carbon atoms, and more particularly, from 2 to 6 carbon atoms,which can be straight-chained or branched and having at least 1 andparticularly from 1 to 2 sites of olefinic unsaturation. Particularalkenyl groups include ethenyl (—CH═CH₂), n-propenyl (—CH₂CH═CH₂),isopropenyl (—C(CH₃)═CH₂) and the like.

‘Amino’ refers to the radical —NH₂.

‘Aryl’ refers to a monovalent aromatic hydrocarbon group derived by theremoval of one hydrogen atom from a single carbon atom of a parentaromatic ring system. In particular aryl refers to an aromatic ringstructure, monocyclic or polycyclic, with the number of ring atomsspecified. Specifically, the term includes groups that include from 6 to10 ring members. Where the aryl group is a monocyclic ring system itpreferentially contains 6 carbon atoms. Particularly aryl groups includephenyl, naphthyl, indenyl, and tetrahydronaphthyl.

‘Cycloalkyl’ refers to a non-aromatic hydrocarbyl ring structure,monocyclic or polycyclic, with the number of ring atoms specified. Acycloalkyl may have from 3 to 10 carbon atoms, and in particular from 3to 7 carbon atoms. Such cycloalkyl groups include, by way of example,single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and cycloheptyl.

‘Cyano’ refers to the radical —CN.

‘Halo’ or ‘halogen’ refers to fluoro (F), chloro (Cl), bromo (Br) andiodo (I). Particular halo groups are either fluoro or chloro.

‘Hetero’ when used to describe a compound or a group present on acompound means that one or more carbon atoms in the compound or grouphave been replaced by a nitrogen, oxygen, or sulfur heteroatom. Heteromay be applied to any of the hydrocarbyl groups described above such asalkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g.heteroaryl, and the like having from 1 to 4, and particularly from 1 to3 heteroatoms, more typically 1 or 2 heteroatoms, for example a singleheteroatom.

‘Heteroaryl’ means an aromatic ring structure, monocyclic or polycyclic,that includes one or more heteroatoms independently selected from O, Nand S and the number of ring atoms specified. In particular, thearomatic ring structure may have from 5 to 10 ring members. Theheteroaryl group can be, for example, a five membered or six memberedmonocyclic ring or a bicyclic structure formed from fused five and sixmembered rings or two fused six membered rings or, by way of a furtherexample, two fused five membered rings. Each ring may contain up to fourheteroatoms typically selected from nitrogen, sulphur and oxygen.Typically the heteroaryl ring will contain up to 4 heteroatoms, moretypically up to 3 heteroatoms, more usually up to 2, for example asingle heteroatom. In one embodiment, the heteroaryl ring contains atleast one ring nitrogen atom. The nitrogen atoms in the heteroaryl ringscan be basic, as in the case of an imidazole or pyridine, or essentiallynon-basic as in the case of an indole or pyrrole nitrogen. In generalthe number of basic nitrogen atoms present in the heteroaryl group,including any amino group substituents of the ring, will be less thanfive. Examples of five membered monocyclic heteroaryl groups include butare not limited to pyrrole, furan, thiophene, imidazole, furazan,oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, isothiazole,thiadiazole, pyrazole, triazole and tetrazole groups. Examples of sixmembered monocyclic heteroaryl groups include but are not limited topyridine, pyrazine, pyridazine, pyrimidine and triazine. Particularexamples of bicyclic heteroaryl groups containing a five membered ringfused to another five membered ring include but are not limited toimidazothiazole and imidazoimidazole. Particular examples of bicyclicheteroaryl groups containing a six membered ring fused to a fivemembered ring include but are not limited to benzofuran, benzothiophene,benzoimidazole, benzoxazole, isobenzoxazole, benzisoxazole,benzthiazole, benzisothiazole, isobenzofuran, indole, isoindole,isoindolone, indolizine, indoline, isoindoline, purine (e.g. adenine,guanine), indazole, imidazopyridines, imidazopyrimidines,imidazopyrazines, pyrazolopyrimidine, triazolopyrimidine, benzodioxoleand pyrazolopyridine groups. Particular examples of bicyclic heteroarylgroups containing two fused six membered rings include but are notlimited to quinoline, isoquinoline, chroman, thiochroman, chromene,isochromene, chroman, isochroman, benzodioxan, quinolizine, benzoxazine,benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline,phthalazine, naphthyridine and pteridine groups. Particular heteroarylgroups are those derived from thiophene, pyrrole, benzothiophene,benzofuran, indole, pyridine, quinoline, imidazole, thiazole, oxazoleand pyrazine.

Examples of representative heteroaryls include the following:

wherein each Y is selected from >C(═O), NH, O and S.

As used herein, the term ‘heterocycloalkyl’ means a stable non-aromaticring structure, monocyclic or polycyclic, that includes one or moreheteroatoms independently selected from O, N and S and the number ofring atoms specified. The non-aromatic ring structure may have from 4 to10 ring members, and in particular from 4 to 7 ring members. A fusedheterocyclic ring system may include carbocyclic rings and need only toinclude one heterocyclic ring. Examples of heterocyclic rings include,but are not limited to, morpholine, piperidine (e.g. 1-piperidinyl,2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g.1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, pyran,tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (e.g.4-tetrahydro pyranyl), imidazoline, imidazolidinone, oxazoline,thiazoline, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazines such as N-methyl piperazine. Further examples includethiomorpholine and its S-oxide and S,S-dioxide (particularlythiomorpholine). Still further examples include azetidine, piperidone,piperazone, and N-alkyl piperidines such as N-methyl piperidine.Particular examples of heterocycloalkyl groups are shown in thefollowing illustrative examples:

wherein each W is selected from CH₂, NH, O and S; and each Y is selectedfrom NH, O, C(═O), SO₂, and S.

As used herein, the term ‘heterocycloalkenyl’ means a‘heterocycloalkyl’, which comprises at least one double bond. Particularexamples of heterocycloalkenyl groups are shown in the followingillustrative examples:

wherein each W is selected from CH₂, NH, O and S; each Y is selectedfrom NH, O, C(═O), SO₂, and S; and each Z is selected from N or CH.

‘Hydroxyl’ refers to the radical —OH.

‘Oxo’ refers to the radical ═O.

‘Substituted’ refers to a group in which one or more hydrogen atoms areeach independently replaced with the same or different substituent(s).

‘Sulfo’ or ‘sulfonic acid’ refers to a radical such as —SO₃H.

‘Thiol’ refers to the group —SH.

As used herein, term ‘substituted with one or more’ refers to one tofour substituents. In one embodiment it refers to one to threesubstituents. In further embodiments it refers to one or twosubstituents. In a yet further embodiment it refers to one substituent.

‘Thioalkoxy’ refers to the group —SR²⁶ where R²⁶ is alkyl with thenumber of carbon atoms specified. Particular thioalkoxy groups arethiomethoxy, thioethoxy, n-thiopropoxy, isothiopropoxy, n-thiobutoxy,tert-thiobutoxy, sec-thiobutoxy, n-thiopentoxy, n-thiohexoxy, and1,2-dimethylthiobutoxy. More particular thioalkoxy groups are lowerthioalkoxy, i.e. with between 1 and 6 carbon atoms. Further particularalkoxy groups have between 1 and 4 carbon atoms.

One having ordinary skill in the art of organic synthesis will recognizethat the maximum number of heteroatoms in a stable, chemically feasibleheterocyclic ring, whether it is aromatic or non aromatic, is determinedby the size of the ring, the degree of unsaturation and the valence ofthe heteroatoms. In general, a heterocyclic ring may have one to fourheteroatoms so long as the heteroaromatic ring is chemically feasibleand stable.

‘Pharmaceutically acceptable’ means approved or approvable by aregulatory agency of the Federal or a state government or thecorresponding agency in countries other than the United States, or thatis listed in the U.S. Pharmacopoeia or other generally recognizedpharmacopoeia for use in animals, and more particularly, in humans.

‘Pharmaceutically acceptable salt’ refers to a salt of a compound of theinvention that is pharmaceutically acceptable and that possesses thedesired pharmacological activity of the parent compound. In particular,such salts are non-toxic may be inorganic or organic acid addition saltsand base addition salts. Specifically, such salts include: (1) acidaddition salts, formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike; or formed with organic acids such as acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g. an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike. Salts further include, by way of example only, sodium, potassium,calcium, magnesium, ammonium, tetraalkylammonium, and the like; and whenthe compound contains a basic functionality, salts of non toxic organicor inorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, acetate, maleate, oxalate and the like. The term‘pharmaceutically acceptable cation’ refers to an acceptable cationiccounter-ion of an acidic functional group. Such cations are exemplifiedby sodium, potassium, calcium, magnesium, ammonium, tetraalkylammoniumcations, and the like.

‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant,excipient or carrier with which a compound of the invention isadministered.

‘Prodrugs’ refers to compounds, including derivatives of the compoundsof the invention, which have cleavable groups and become by solvolysisor under physiological conditions the compounds of the invention whichare pharmaceutically active in vivo. Such examples include, but are notlimited to, choline ester derivatives and the like, N-alkylmorpholineesters and the like.

‘Solvate’ refers to forms of the compound that are associated with asolvent, usually by a solvolysis reaction. This physical associationincludes hydrogen bonding. Conventional solvents include water, ethanol,acetic acid and the like. The compounds of the invention may be preparede.g. in crystalline form and may be solvated or hydrated. Suitablesolvates include pharmaceutically acceptable solvates, such as hydrates,and further include both stoichiometric solvates and non-stoichiometricsolvates. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. ‘Solvate’ encompasses bothsolution-phase and isolable solvates. Representative solvates includehydrates, ethanolates and methanolates.

‘Subject’ includes humans. The terms ‘human’, ‘patient’ and ‘subject’are used interchangeably herein.

‘Effective amount’ means the amount of a compound of the invention that,when administered to a subject for treating a disease, is sufficient toeffect such treatment for the disease. The ‘effective amount’ can varydepending on the compound, the disease and its severity, and the age,weight, etc., of the subject to be treated.

‘Preventing’ or ‘prevention’ refers to a reduction in risk of acquiringor developing a disease or disorder (i.e. causing at least one of theclinical symptoms of the disease not to develop in a subject that may beexposed to a disease-causing agent, or predisposed to the disease inadvance of disease onset).

The term ‘prophylaxis’ is related to ‘prevention’, and refers to ameasure or procedure the purpose of which is to prevent, rather than totreat or cure a disease. Non-limiting examples of prophylactic measuresmay include the administration of vaccines; the administration of lowmolecular weight heparin to hospital patients at risk for thrombosisdue, for example, to immobilization; and the administration of ananti-malarial agent such as chloroquine, in advance of a visit to ageographical region where malaria is endemic or the risk of contractingmalaria is high.

‘Treating’ or ‘treatment’ of any disease or disorder refers, in oneembodiment, to ameliorating the disease or disorder (i.e. arresting thedisease or reducing the manifestation, extent or severity of at leastone of the clinical symptoms thereof). In another embodiment ‘treating’or ‘treatment’ refers to ameliorating at least one physical parameter,which may not be discernible by the subject. In yet another embodiment,‘treating’ or ‘treatment’ refers to modulating the disease or disorder,either physically (e.g. stabilization of a discernible symptom),physiologically (e.g. stabilization of a physical parameter), or both.In a further embodiment, ‘treating’ or ‘treatment’ relates to slowingthe progression of the disease.

As used herein the term ‘fibrotic diseases’ refers to diseasescharacterized by excessive scarring due to excessive production,deposition, and contraction of extracellular matrix, and are that areassociated with the abnormal accumulation of cells and/or fibronectinand/or collagen and/or increased fibroblast recruitment and include butare not limited to fibrosis of individual organs or tissues such as theheart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue,skin, cornea, retina, musculoskeletal and digestive tract. Inparticular, the term fibrotic diseases refers to idiopathic pulmonaryfibrosis (IPF); cystic fibrosis, other diffuse parenchymal lung diseasesof different etiologies including iatrogenic drug-induced fibrosis,occupational and/or environmental induced fibrosis, granulomatousdiseases (sarcoidosis, hypersensitivity pneumonia), collagen vasculardisease, alveolar proteinosis, langerhans cell granulomatosis,lymphangioleiomyomatosis, inherited diseases (Hermansky-Pudlak Syndrome,tuberous sclerosis, neurofibromatosis, metabolic storage disorders,familial interstitial lung disease); radiation induced fibrosis; chronicobstructive pulmonary disease (COPD); scleroderma; bleomycin inducedpulmonary fibrosis; chronic asthma; silicosis; asbestos inducedpulmonary fibrosis; acute respiratory distress syndrome (ARDS); kidneyfibrosis; tubulointerstitium fibrosis; glomerular nephritis; focalsegmental glomerular sclerosis; IgA nephropathy; hypertension; Alport;gut fibrosis; liver fibrosis; cirrhosis; alcohol induced liver fibrosis;toxic/drug induced liver fibrosis; hemochromatosis; nonalcoholicsteatohepatitis (NASH); biliary duct injury; primary biliary cirrhosis;infection induced liver fibrosis; viral induced liver fibrosis; andautoimmune hepatitis; corneal scarring; hypertrophic scarring; Dupuytrendisease, keloids, cutaneous fibrosis; cutaneous scleroderma; systemicsclerosis, spinal cord injury/fibrosis; myelofibrosis; vascularrestenosis; atherosclerosis; arteriosclerosis; Wegener's granulomatosis;Peyronie's disease, or chronic lymphocytic. More particularly, the term‘fibrotic diseases’ refers to idiopathic pulmonary fibrosis (IPF).

As used herein the term ‘proliferative disease(s)’ refers to conditionssuch as cancer (e.g. uterine leiomyosarcoma or prostate cancer),myeloproliferative disorders (e.g. polycythemia vera, essentialthrombocytosis and myelofibrosis), leukemia (e.g. acute myeloidleukaemia, acute and chronic lymphoblastic leukemia), multiple myeloma,psoriasis, restenosis, scleroderma or fibrosis. In particular the termrefers to cancer, leukemia, multiple myeloma and psoriasis.

As used herein, the term ‘cancer’ refers to a malignant or benign growthof cells in skin or in body organs, for example but without limitation,breast, prostate, lung, kidney, pancreas, stomach or bowel. A cancertends to infiltrate into adjacent tissue and spread (metastasise) todistant organs, for example to bone, liver, lung or the brain. As usedherein the term cancer includes both metastatic tumour cell types (suchas but not limited to, melanoma, lymphoma, leukaemia, fibrosarcoma,rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (suchas but not limited to, colorectal cancer, prostate cancer, small celllung cancer and non-small cell lung cancer, breast cancer, pancreaticcancer, bladder cancer, renal cancer, gastric cancer, glioblastoma,primary liver cancer, ovarian cancer, prostate cancer and uterineleiomyosarcoma). In particular, the term “cancer’ refers to acutelymphoblastic leukemia, acute myeloidleukemia, adrenocortical carcinoma,anal cancer, appendix cancer, astrocytomas, atypical teratoid/rhabdoidtumor, basal cell carcinoma, bile duct cancer, bladder cancer, bonecancer (osteosarcoma and malignant fibrous histiocytoma), brain stemglioma, brain tumors, brain and spinal cord tumors, breast cancer,bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocyticleukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer,craniopharyngioma, cutaneous T-Cell lymphoma, embryonal tumors,endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer,ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladdercancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor,gastrointestinal stromal tumor (GIST), gastrointestinal stromal celltumor, germ cell tumor, glioma, hairy cell leukemia, head and neckcancer, hepatocellular (liver) cancer, hodgkin lymphoma, hypopharyngealcancer, intraocular melanoma, islet cell tumors (endocrine pancreas),Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngealcancer, leukemia, Acute lymphoblastic leukemia, acute myeloid leukemia,chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cellleukemia, liver cancer, non-small cell lung cancer, small cell lungcancer, Burkitt lymphoma, cutaneous T-celllymphoma, Hodgkin lymphoma,non-Hodgkin lymphoma, lymphoma, Waldenstrom macroglobulinemia,medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouthcancer, chronic myelogenous leukemia, myeloid leukemia, multiplemyeloma, asopharyngeal cancer, neuroblastoma, non-small cell lungcancer, oral cancer, oropharyngeal cancer, osteosarcoma, malignantfibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer,ovarian germ cell tumor, ovarian low malignant potential tumor,pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer,pharyngeal cancer, pineal parenchymal tumors of intermediatedifferentiation, pineoblastoma and supratentorial primitiveneuroectodermal tumors, pituitary tumor, plasma cell neoplasm/multiplemyeloma, pleuropulmonary blastoma, primary central nervous systemlymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer,retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewingsarcoma family of tumors, sarcoma, kaposi, Sezary syndrome, skin cancer,small cell Lung cancer, small intestine cancer, soft tissue sarcoma,squamous cell carcinoma, stomach (gastric) cancer, supratentorialprimitive neuroectodermal tumors, T-cell lymphoma, testicular cancer,throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethralcancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer,Waldenstrom macroglobulinemia, and Wilms tumor

As used herein the term ‘leukemia’ refers to neoplastic diseases of theblood and blood forming organs. Such diseases can cause bone marrow andimmune system dysfunction, which renders the host highly susceptible toinfection and bleeding. In particular the term leukemia refers to acutemyeloid leukaemia (AML), and acute lymphoblastic leukemia (ALL) andchronic lymphoblastic leukaemia (CLL).

As used herein the term ‘inflammatory diseases’ refers to the group ofconditions including, rheumatoid arthritis, osteoarthritis, juvenileidiopathic arthritis, psoriasis, psoriatic arthritis, allergic airwaydisease (e.g. asthma, rhinitis), chronic obstructive pulmonary disease(COPD), inflammatory bowel diseases (e.g. Crohn's disease, ulcerativecolitis), endotoxin-driven disease states (e.g. complications afterbypass surgery or chronic endotoxin states contributing to e.g. chroniccardiac failure), and related diseases involving cartilage, such as thatof the joints. Particularly the term refers to rheumatoid arthritis,osteoarthritis, allergic airway disease (e.g. asthma), chronicobstructive pulmonary disease (COPD) and inflammatory bowel diseases(e.g. Crohn's disease and ulcerative colitis). More particularly theterm refers to rheumatoid arthritis, and chronic obstructive pulmonarydisease (COPD).

As used herein the term ‘autoimmune disease(s)’ refers to the group ofdiseases including obstructive airways disease, including conditionssuch as COPD, asthma (e.g intrinsic asthma, extrinsic asthma, dustasthma, infantile asthma) particularly chronic or inveterate asthma (forexample late asthma and airway hyperreponsiveness), bronchitis,including bronchial asthma, systemic lupus erythematosus (SLE),cutaneous lupus erythrematosis, lupus nephritis, dermatomyositis,Sjogren's syndrome, multiple sclerosis, psoriasis, dry eye disease, typeI diabetes mellitus and complications associated therewith, atopiceczema (atopic dermatitis), thyroiditis (Hashimoto's and autoimmunethyroiditis), contact dermatitis and further eczematous dermatitis,inflammatory bowel disease (e.g. Crohn's disease and ulcerativecolitis), atherosclerosis and amyotrophic lateral sclerosis.Particularly the term refers to COPD, asthma, systemic lupuserythematosis, type I diabetes mellitus and inflammatory bowel disease.

As used herein, the term ‘respiratory disease’ refers to diseasesaffecting the organs that are involved in breathing, such as the nose,throat, larynx, eustachian tubes, trachea, bronchi, lungs, relatedmuscles (e.g., diaphram and intercostals), and nerves. In particular,examples of respiratory diseases include asthma, adult respiratorydistress syndrome and allergic (extrinsic) asthma, non-allergic(intrinsic) asthma, acute severe asthma, chronic asthma, clinicalasthma, nocturnal asthma, allerGen-induced asthma, aspirin-sensitiveasthma, exercise-induced asthma, isocapnic hyperventilation, child onsetasthma, adult-onset asthma, cough-variant asthma, occupational asthma,steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis,perennial allergic rhinitis, chronic obstructive pulmonary disease,including chronic bronchitis or emphysema, pulmonary hypertension,interstitial lung fibrosis and/or airway inflammation, cystic fibrosis,and hypoxia.

As used herein the term ‘allergy’ refers to the group of conditionscharacterized by a hypersensitivity disorder of the immune systemincluding, allergic airway disease (e.g. asthma, rhinitis), sinusitis,eczema and hives, as well as food allergies or allergies to insectvenom.

As used herein the term ‘asthma’ as used herein refers to any disorderof the lungs characterized by variations in pulmonary gas flowassociated with airway constriction of whatever cause (intrinsic,extrinsic, or both; allergic or non-allergic). The term asthma may beused with one or more adjectives to indicate the cause.

As used herein the term ‘cardiovascular disease’ refers to diseasesaffecting the heart or blood vessels or both. In particular,cardiovascular disease includes arrhythmia (atrial or ventricular orboth); atherosclerosis and its sequelae; angina; cardiac rhythmdisturbances; myocardial ischemia; myocardial infarction; cardiac orvascular aneurysm; vasculitis, stroke; peripheral obstructivearteriopathy of a limb, an organ, or a tissue; reperfusion injuryfollowing ischemia of the brain, heart, kidney or other organ or tissue;endotoxic, surgical, or traumatic shock; hypertension, valvular heartdisease, heart failure, abnormal blood pressure, vasoconstriction(including that associated with migraines); vascular abnormality,inflammation, insufficiency limited to a single organ or tissue.

As used herein the term ‘neurodegenerative diseases’ refers to disordersthat are associated with atrophy of the affected central or peripheralstructures of the nervous system. In particular, the term‘neurodegenerative diseases’ refers to diseases such as Alzheimer'sdisease and other dementias, degenerative nerve diseases, encephalitis,epilepsy, genetic brain disorders, head and brain malformations,hydrocephalus, stroke, Parkinson's disease, multiple sclerosis,amyotrophic lateral sclerosis (ALS or Lou Gehrig's Disease),Huntington's disease, and prion diseases.

As used herein the term ‘dermatological disorder’ refers to a skindisorder. In particular, dermatological disorders include proliferativeor inflammatory disorders of the skin such as, atopic dermatitis,bullous disorders, collagenoses, psoriasis, psoriatic lesions,dermatitis, contact dermatitis, eczema, pruritus, urticaria, rosacea,scleroderma, wound healing, scarring, hypertrophic scarring, keloids,Kawasaki Disease, rosacea, Sjogren-Larsso Syndrome, or urticaria.

As used herein the term ‘abnormal angiogenesis associated disease’refers to diseases caused by the dysregulation of the processesmediating angiogenesis. In particular, abnormal angiogenesis associateddisease refers to atherosclerosis, hypertension, tumor growth,inflammation, rheumatoid arthritis, wet-form macular degeneration,choroidal neovascularization, retinal neovascularization, and diabeticretinopathy.

‘Compound(s) of the invention’, and equivalent expressions, are meant toembrace compounds of the Formula(e) as herein described, whichexpression includes the pharmaceutically acceptable salts, and thesolvates, e.g. hydrates, and the solvates of the pharmaceuticallyacceptable salts where the context so permits. Similarly, reference tointermediates, whether or not they themselves are claimed, is meant toembrace their salts, and solvates, where the context so permits.

When ranges are referred to herein, for example but without limitation,C₁₋₈ alkyl, the citation of a range should be considered arepresentation of each member of said range.

Other derivatives of the compounds of this invention have activity inboth their acid and acid derivative forms, but in the acid sensitiveform often offers advantages of solubility, tissue compatibility, ordelayed release in the mammalian organism (Bundgard, H, 1985). Prodrugsinclude acid derivatives well know to practitioners of the art, such as,for example, esters prepared by reaction of the parent acid with asuitable alcohol, or amides prepared by reaction of the parent acidcompound with a substituted or unsubstituted amine, or acid anhydrides,or mixed anhydrides. Simple aliphatic or aromatic esters, amides andanhydrides derived from acidic groups pendant on the compounds of thisinvention are particularly useful prodrugs. In some cases it isdesirable to prepare double ester type prodrugs such as (acyloxy)alkylesters or ((alkoxycarbonyl)oxy)alkylesters. Particular such prodrugs arethe C₁₋₈ alkyl, C₂₋₈ alkenyl, C₆₋₁₀ optionally substituted aryl, and(C₆₋₁₀ aryl)-(C₁₋₄ alkyl) esters of the compounds of the invention.

As used herein, the term ‘isotopic variant’ refers to a compound thatcontains unnatural proportions of isotopes at one or more of the atomsthat constitute such compound. For example, an ‘isotopic variant’ of acompound can contain one or more non-radioactive isotopes, such as forexample, deuterium (²H or D), carbon-13 (¹³C), nitroGen-15 (¹⁵N), or thelike. It will be understood that, in a compound where such isotopicsubstitution is made, the following atoms, where present, may vary, sothat for example, any hydrogen may be ²H/D, any carbon may be ¹³C, orany nitrogen may be ¹⁵N, and that the presence and placement of suchatoms may be determined within the skill of the art. Likewise, theinvention may include the preparation of isotopic variants withradioisotopes, in the instance for example, where the resultingcompounds may be used for drug and/or substrate tissue distributionstudies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e.¹⁴C, are particularly useful for this purpose in view of their ease ofincorporation and ready means of detection. Further, compounds may beprepared that are substituted with positron emitting isotopes, such as¹¹C, ¹⁸F, ¹⁵O and ¹³N, and would be useful in Positron EmissionTopography (PET) studies for examining substrate receptor occupancy.

All isotopic variants of the compounds provided herein, radioactive ornot, are intended to be encompassed within the scope of the invention.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed ‘isomers’. Isomersthat differ in the arrangement of their atoms in space are termed‘stereoisomers’.

Stereoisomers that are not mirror images of one another are termed‘diastereomers’ and those that are non-superimposable mirror images ofeach other are termed ‘enantiomers’. When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e. as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a ‘racemic mixture’.

‘Tautomers’ refer to compounds that are interchangeable forms of aparticular compound structure, and that vary in the displacement ofhydrogen atoms and electrons. Thus, two structures may be in equilibriumthrough the movement of π electrons and an atom (usually H). Forexample, enols and ketones are tautomers because they are rapidlyinterconverted by treatment with either acid or base. Another example oftautomerism is the aci- and nitro-forms of phenylnitromethane, that arelikewise formed by treatment with acid or base.

Tautomeric forms may be relevant to the attainment of the optimalchemical reactivity and biological activity of a compound of interest.

The compounds of the invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R- or(S)-stereoisomers or as mixtures thereof.

Unless indicated otherwise, the description or naming of a particularcompound in the specification and claims is intended to include bothindividual enantiomers and mixtures, racemic or otherwise, thereof. Themethods for the determination of stereochemistry and the separation ofstereoisomers are well-known in the art.

It will be appreciated that compounds of the invention may bemetabolized to yield biologically active metabolites.

THE INVENTION

The present invention is based on the identification of novel compounds,and their ability to act as inhibitors of autotaxin and that they may beuseful for the treatment of fibrotic diseases, proliferative diseases,inflammatory diseases, autoimmune diseases, respiratory diseases,cardiovascular diseases, neurodegenerative diseases, dermatologicaldisorders, and/or abnormal angiogenesis associated diseases.

The present invention also provides methods for the production of thesecompounds, pharmaceutical compositions comprising these compounds andmethods of treatment for fibrotic diseases, proliferative diseases,inflammatory diseases, autoimmune diseases, respiratory diseases,cardiovascular diseases, neurodegenerative diseases, dermatologicaldisorders, and/or abnormal angiogenesis associated diseases byadministering the compounds of the invention.

Accordingly, in a first aspect of the invention, the compounds of theinvention are provided having a Formula (I):

-   -   wherein    -   R^(1a) is H, halo or C₁₋₄ alkyl;    -   R^(1b) is:        -   halo,        -   C₁₋₄ alkyl (which alkyl is optionally substituted with one            or more independently selected halo), or        -   C₁₋₄ alkoxy (which alkoxy is optionally substituted with one            or more independently selected halo);    -   X is —S—, —O—, —N═CH—, —CH═N— or —CH═CH—;    -   W is N, or CR³    -   when W is N, R² is:        -   H,        -   —CN,        -   halo,        -   C₁₋₄ alkyl (which alkyl is optionally substituted with one            or more independently selected OH, or CN),        -   —C(═O)CH₃,        -   —C(═O)CF₃,        -   —C(═O)OCH₃,        -   —C(═O)NH₂, or        -   —NHC(═O)CH₃, or    -   when W is CR³, one of R² or R³ is:        -   H,        -   —CN,        -   halo,        -   C₁₋₄ alkyl (which alkyl is optionally substituted with one            or more independently selected OH, or CN)        -   —C(═O)CH₃,        -   —C(═O)CF₃,        -   —C(═O)OCH₃,        -   —C(═O)NH₂, or        -   —NHC(═O)CH₃,    -   and the other is H, or C₁₋₄ alkyl;    -   R⁴ is C₁₋₄ alkyl;    -   R⁵ is C₁₋₄ alkyl optionally substituted with one or more        independently selected CN, OH, halo, or —C(═O)NH₂;    -   one of R^(6a) or R^(6b) is selected from H, —CH₃, and halo, and        the other is H;    -   Cy is:        -   C₄₋₁₀ cycloalkyl,        -   4-10 membered mono or bicyclic heterocycloalkyl containing            one or more heteroatoms independently selected from O, N,            and S, or        -   4-7 membered heterocycloalkenyl containing 1 double bond,            containing one or more heteroatoms independently selected            from O, N, and S;    -   each R⁷ is independently selected from:        -   OH,        -   oxo,        -   halo, and        -   C₁₋₄ alkyl (which alkyl is optionally substituted with one            or more independently selected OH, or C₁₋₄ alkoxy);    -   the subscript a is 0, 1 or 2;    -   R⁸ is -(L₁-W₁)_(m)-L₂-G₁,    -   wherein        -   L₁ is absent, or is —O—, —C(═O)—, —NR^(i), —NR^(h)C(═O)—, or            —SO₂—;        -   W₁ is C₁₋₄ alkylene;        -   the subscript m is 0, or 1;        -   L₂ is absent, or is —O—, —C(═O)—, —C(═O)O—, —OC(═O)—,            —C(═O)—C(═O)—, —C(═O)—C(═O)NR^(a)—, —NR^(b)—, —C(═O)NR^(c)—,            —NR^(d)C(═O)—, —NR^(j)C(═O)O—, —SO₂—, —SO₂NR^(e)— or            —NR^(f)SO₂—;        -   G is            -   H,            -   —CN,            -   C₁₋₄ alkyl (which alkyl is optionally substituted with                one or more independently selected —CN, OH, halo or                phenyl),            -   C₃₋₇ cycloalkyl (which cycloalkyl is optionally                substituted with —NH₂),            -   5-6 membered heterocycloalkenyl containing 1 double bond                containing one or more heteroatoms independently                selected from O, N, and S (which heterocycloalkenyl is                optionally substituted with one or more independently                selected R⁹ groups),            -   4-10 membered mono, bi or spirocyclic heterocycloalkyl                containing one or more heteroatoms independently                selected from O, N, and S (which heterocycloalkyl is                optionally substituted with one or more independently                selected R⁹ groups), or            -   5-6 membered heteroaryl containing one or more                heteroatoms independently selected from O, N, and S                (which heteroaryl is optionally substituted with one or                more independently selected R¹⁰ groups),    -   each R⁹ is oxo, or R¹⁰;    -   each R¹⁰ is:        -   —OH,        -   halo,        -   —CN,        -   C₁₋₄ alkyl (which alkyl is optionally substituted with one            or more independently selected OH, halo, or phenyl),        -   C₁₋₄ alkoxy,        -   C₃₋₇ cycloalkyl,        -   phenyl,        -   —SO₂CH₃,        -   —C(═O)C₁₋₄ alkoxy,        -   —C(═O)C₁₋₄ alkyl, or        -   —NR^(g)C(═O)C₁₋₄ alkyl; and    -   each R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), R^(h),        R^(i), and R^(j) is independently selected from H and C₁₋₄        alkyl.

In one embodiment, a compound of the invention is according to FormulaI, wherein R^(1a) is H.

In one embodiment, a compound of the invention is according to FormulaI, wherein R^(1a) is halo. In a particular embodiment, R^(1a) is F, Cl,or Br. In a more particular embodiment, R^(1a) is F, or Cl. In a mostparticular embodiment, R^(1a) is F.

In one embodiment, a compound of the invention is according to FormulaI, wherein R^(1a) is C₁₋₄ alkyl. In a particular embodiment, R^(1a) is—CH₃, —CH₂—CH₃, —CH₂—CH₂—CH₃, —CH(CH₃)₂. In a more particularembodiment, R^(1a) is —CH₃, or —CH₂—CH₃.

In one embodiment, a compound of the invention is according to FormulaI, wherein R^(1b) is halo. In a particular embodiment, R^(1b) is F, Cl,or Br. In a more particular embodiment, R^(1b) is F, or Cl. In a mostparticular embodiment, R^(1b) is F.

In one embodiment, a compound of the invention is according to FormulaI, wherein R^(1b) is C₁₋₄ alkyl. In a particular embodiment, R^(1b) is—CH₃, —CH₂—CH₃, —CH₂—CH₂—CH₃, —CH(CH₃)₂. In a more particularembodiment, R^(1b) is —CH₃, or —CH₂—CH₃.

In one embodiment, a compound of the invention is according to FormulaI, wherein R^(1b) is C₁₋₄ alkyl substituted with one or moreindependently selected halo. In a particular embodiment, R^(1b) is —CF₃,or —CH₂—CF₃. In a more particular embodiment, R^(1b) is —CF₃.

In one embodiment, a compound of the invention is according to FormulaI, wherein R^(1b) is C₁₋₄ alkoxy. In a particular embodiment, R^(1b) is—OCH₃, —OCH₂—CH₃, —OCH₂—CH₂—CH₃, —OCH(CH₃)₂. In a more particularembodiment, R^(1b) is —OCH₃, or —OCH₂—CH₃. In a most particularembodiment, R^(1b) is —OCH₃.

In one embodiment, a compound of the invention is according to FormulaI, wherein R^(1b) is C₁₋₄ alkoxy substituted with one or moreindependently selected halo. In a more particular embodiment, R^(1b) is—OCF₃, —OCH₂—CHF₂ or —OCH₂—CF₃. In a most particular embodiment, R^(1b)is —OCF₃.

In one embodiment, a compound of the invention is according to FormulaI, wherein X is —S—, —O—, —N═CH—, —CH═N— or —CH═CH—. In a particularembodiment, X is —S—, or —O—. In another particular embodiment, X is—N═CH—.

In one embodiment, a compound of the invention is according to FormulaI, wherein W is N, and R² is as previously defined. In a particularembodiment, R² is H, —CN, —C(═O)CH₃, —C(═O)CF₃, —C(═O)OCH₃, —C(═O)NH₂,or —NHC(═O)CH₃. In a more particular embodiment, R² is —CN.

In one embodiment, a compound of the invention is according to FormulaI, wherein W is N, and R² is as previously defined. In a particularembodiment, R² is halo. In a more particular embodiment, R² is F, Cl, orBr. In a most particular embodiment, R² is F, or Cl.

In one embodiment, a compound of the invention is according to FormulaI, wherein W is N, and R² is as previously defined. In a particularembodiment, R² is C₁₋₄ alkyl. In another particular embodiment, R² isC₁₋₄ alkyl substituted with one or more independently selected OH, andCN. In yet another particular embodiment, R² is C₁₋₄ alkyl substitutedwith one OH, or CN. In a more particular embodiment, R² is —CH₃,—CH₂—CH₃, —CH₂—OH, or —CH₂—CN. In a most particular embodiment, R² is—CH₂—OH, or —CH₂—CN.

In another embodiment, a compound of the invention is according toFormula I, wherein W is CR³, and R² and R³ are as previously defined. Ina particular embodiment, R² is H, —CN, —C(═O)CH₃, —C(═O)CF₃, —C(═O)OCH₃,—C(═O)NH₂, or —NHC(═O)CH₃, and R³ is H, or C₁₋₄ alkyl. In anotherparticular embodiment, R² is H, or C₁₋₄ alkyl, and R³ is H, —CN,—C(═O)CH₃, —C(═O)CF₃, —C(═O)OCH₃, —C(═O)NH₂, or —NHC(═O)CH₃. In a moreparticular embodiment, R² is H, —CN, —C(═O)CH₃, —C(═O)CF₃, —C(═O)OCH₃,—C(═O)NH₂, or —NHC(═O)CH₃, and R³ is H, —CH₃, or —CH₂—CH₃. In anothermore particular embodiment, R² is H, —CH₃, or —CH₂—CH₃, and R³ is H,—CN, —C(═O)CH₃, —C(═O)CF₃, —C(═O)OCH₃, —C(═O)NH₂, or —NHC(═O)CH₃. In amost particular embodiment, R² is —CN, and R³ is H, —CH₃, or —CH₂—CH₃.In another most particular embodiment, R² is H, —CH₃, or —CH₂—CH₃, andR³ is —CN.

In another embodiment, a compound of the invention is according toFormula I, wherein W is CR³, and R² and R³ are as previously defined. Ina particular embodiment, R² is halo, and R³ is H, or C₁₋₄ alkyl. Inanother particular embodiment, R² is H, or C₁₋₄ alkyl, and R³ is halo.In a more particular embodiment, R² is F, Cl, or Br, and R³ is H, —CH₃,or —CH₂—CH₃. In another more particular embodiment, R² is H, —CH₃, or—CH₂—CH₃, and R³ is F, Cl, or Br. In a most particular embodiment, R² isF, or Cl, and R³ is H, —CH₃, or —CH₂—CH₃. In another most particularembodiment, R² is H, —CH₃, or —CH₂—CH₃, and R³ is F, or Cl.

In another embodiment, a compound of the invention is according toFormula I, wherein W is CR³, and R² and R³ are as previously defined. Ina particular embodiment, R² is C₁₋₄ alkyl, and R³ is H, or C₁₋₄ alkyl.In another particular embodiment, R² is H, or C₁₋₄ alkyl, and R³ is C₁₋₄alkyl. In a more particular embodiment, R² is —CH₃, or —CH₂—CH₃, and R³is H, —CH₃, or —CH₂—CH₃. In another more particular embodiment, R² is H,—CH₃, or —CH₂—CH₃, and R³ is —CH₃, or —CH₂—CH₃.

In another embodiment, a compound of the invention is according toFormula I, wherein W is CR³, and R² and R³ are as previously defined. Ina particular embodiment, R² is C₁₋₄ alkyl substituted with OH, or CN,and R³ is H, or C₁₋₄ alkyl. In another particular embodiment, R² is H,or C₁₋₄ alkyl, and R³ is C₁₋₄ alkyl substituted with OH, or CN. In amore particular embodiment, R² is —CH₂—OH, or —CH₂—CN, and R³ is H,—CH₃, or —CH₂—CH₃. In another more particular embodiment, R² is H, —CH₃,or —CH₂—CH₃, and R³ is —CH₂—OH, or —CH₂—CN.

In one embodiment, a compound of the invention is according to FormulaII:

wherein the subscript a, R⁴, R⁵, R^(6a), R^(6b), R⁷ and R⁸ are asdescribed above.

In another embodiment, a compound of the invention is according toFormula III:

wherein the subscript a, R⁴, R⁵, R^(6a), R^(6b), R⁷ and R⁸ are asdescribed above.

In one embodiment, a compound of the invention is according to FormulaI, II or III, wherein R⁴ is C₁₋₄ alkyl. In a particular embodiment, R⁴is —CH₃, or —CH₂—CH₃. In a more particular embodiment, R⁴ is —CH₃.

In one embodiment, a compound of the invention is according to FormulaI, II or III, wherein R⁵ is C₁₋₄ alkyl. In a particular embodiment, R⁵is —CH₃, —CH₂—CH₃ or —CH₂—CH₂—CH₃. In a more particular embodiment, R⁵is —CH₃, or —CH₂—CH₃. In a most particular embodiment, R⁵ is —CH₂—CH₃.

In one embodiment, a compound of the invention is according to FormulaI, II or III, wherein R⁵ is C₁₋₄ alkyl substituted with one or moreindependently selected CN, OH, halo, and —C(═O)NH₂. In a particularembodiment, R⁵ is C₁₋₄ alkyl substituted with one CN, OH, halo, or—C(═O)NH₂. In a more particular embodiment, R⁵ is —CH₃, —CH₂—CH₃,—CH₂—CH₂—CH₃, —CH₂—CH₂—CH₂—CH₃, —CH(CH₃)₂, or —CH₂—CH(CH₃)₂, each ofwhich is substituted with one CN, OH, halo, or —C(═O)NH₂. In anothermore particular embodiment, R⁵ is —CH₃, —CH₂—CH₃, —CH₂—CH₂—CH₃,—CH₂—CH₂—CH₂—CH₃, or —CH₂—CH(CH₃)₂, each of which is substituted withone —CN, OH, F, or —C(═O)NH₂. In a most particular embodiment, R⁵ is—CH₂—CH₂—CN, —CH₂—CH₂—OH, —CH₂—CF₃, or —CH₂—CH₂—C(═O)NH₂.

In one embodiment, a compound of the invention is according to FormulaI, II or III, wherein Cy is C₃₋₁₀ cycloalkyl. In a particularembodiment, Cy is cyclobutyl, cyclopentyl or cyclohexyl. In a moreparticular embodiment, Cy is cyclohexyl.

In one embodiment, a compound of the invention is according to FormulaI, II or III, wherein Cy is 4-10 membered mono or bicyclicheterocycloalkyl containing one or more heteroatoms independentlyselected from O, N, and S. In a particular embodiment, Cy is oxetanyl,azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl,piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl. In a moreparticular embodiment, Cy is piperidinyl. In another more particularembodiment, Cy is piperazinyl.

In one embodiment, a compound of the invention is according to FormulaI, II or III, wherein Cy is 4-7 membered heterocycloalkenyl containing 1double bond, containing one or more heteroatoms independently selectedfrom O, N, and S. In a particular embodiment, Cy is dihydrofuranyl,dihydrothiazolyl, dihydrooxazolyl, dihydropyranyl, tetrahydropyridinyl,or dihydrothiopyranyl. In a more particular embodiment, Cy isdihydrooxazolyl.

In one embodiment, a compound of the invention is according to FormulaI, II or III, wherein the subscript a is 1 or 2, and R⁷ is OH, oxo, orhalo. In a particular embodiment, R⁷ is OH, oxo, F, or Cl.

In one embodiment, a compound of the invention is according to FormulaI, II or III, wherein the subscript a is 1 or 2, and R⁷ is C₁₋₄ alkyl.In a particular embodiment, R⁷ is —CH₃, —CH₂—CH₃, or —CH(CH₃)₂. In amore particular embodiment, R⁷ is —CH₃.

In one embodiment, a compound of the invention is according to FormulaI, II or III, wherein the subscript a is 1 or 2, and R⁷ is C₁₋₄ alkylsubstituted with OH, or C₁₋₄ alkoxy. In a particular embodiment, R⁷ is—CH₃, —CH₂—CH₃, or —CH(CH₃)₂, each of which is substituted with OH, orC₁₋₄ alkoxy. In a more particular embodiment, R⁷ is —CH₂—OH, or—CH₂—OCH₃.

In one embodiment, a compound of the invention is according to FormulaI, II or III, wherein the subscript a is 0.

In one embodiment, a compound of the invention is according to FormulaIVa, IVb, Vc or IVd:

wherein R^(6a), R^(6b), L₁, W₁, L₂, G₁ and the subscript m are aspreviously described.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein the subscript m is 1, and L₁ is absent.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein the subscript m is 1, L₁ is —NR^(i)—, and R^(i) is aspreviously described. In a particular embodiment, R^(i) is H. In anotherparticular embodiment, R^(i) is —CH₃, —CH₂—CH₃, or —CH(CH₃)₂.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein the subscript m is 1, L₁ is —NR^(h)C(═O)—, and R^(h) isas previously described. In a particular embodiment, R^(h) is H. Inanother particular embodiment, R^(h) is —CH₃, —CH₂—CH₃, or —CH(CH₃)₂.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein the subscript m is 1, and L₁ is —C(═O)—, or —SO₂—.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein the subscript m is 1, and W₁ is C₁₋₄ alkylene. In aparticular embodiment, W₁ is —CH₂—, —CH₂—CH₂—, —C(CH₃)H—, —CH₂—CH₂—CH₂—or —CH₂—C(CH₃)H—. In a more particular embodiment, W₁ is —CH₂—, or—C(CH₃)H—.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein the subscript m is 0.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein L₂ is absent.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein L₂ is —O—.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein L₂ is —O—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)—C(═O)—, or—SO₂—.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein L₂ is —C(═O)—C(═O)NR^(a)—, and R^(a) is as previouslydescribed. In a particular embodiment, R^(a) is H. In another particularembodiment, R^(a) is —CH₃, —CH₂—CH₃, or —CH(CH₃)₂.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein L₂ is —NR^(b)—, and R^(b) is as previously described. Ina particular embodiment, R^(b) is H. In another particular embodiment,R^(b) is —CH₃, —CH₂—CH₃, or —CH(CH₃)₂.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein L₂ is —C(═O)NR^(c)—, and R^(c) is as previouslydescribed. In a particular embodiment, R^(c) is H. In another particularembodiment, R^(c) is —CH₃, —CH₂—CH₃, or —CH(CH₃)₂.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein L₂ is —NR^(d)C(═O)—, and R^(d) is as previouslydescribed. In a particular embodiment, R^(d) is H. In another particularembodiment, R^(d) is —CH₃, —CH₂—CH₃, or —CH(CH₃)₂.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein L₂ is —NR^(j)C(═O)O—, and R^(j) is as previouslydescribed. In a particular embodiment, R^(j) is H. In another particularembodiment, R^(j) is —CH₃, —CH₂—CH₃, or —CH(CH₃)₂.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein L₂ is —SO₂NR^(e)—, and R^(e) is as previously described.In a particular embodiment, R^(e) is H. In another particularembodiment, R^(e) is —CH₃, —CH₂—CH₃, or —CH(CH₃)₂.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein L₂ is —NR^(f)SO₂—, and R^(f) is as previously described.In a particular embodiment, R^(f) is H. In another particularembodiment, R^(f) is —CH₃, —CH₂—CH₃, or —CH(CH₃)₂.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein G₁ is H, or CN.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein G₁ is C₁₋₄ alkyl. In a particular embodiment, G₁ is —CH₃,or —CH₂—CH₃.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein G₁ is C₁₋₄ alkyl substituted with —CN, OH, halo orphenyl. In a particular embodiment, G₁ is —CH₃, —CH₂—CH₃, or —CH(CH₃)₂,each of which is substituted with —CN, OH, halo or phenyl. In a moreparticular embodiment, G₁ is —CF₃, —CH₂—Cl, —CH₂—CN, —CH₂—OH or —CH₂-Ph.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein G₁ is C₃₋₇ cycloalkyl. In a particular embodiment, G₁ iscyclopropyl, cyclobutyl, cyclopropyl, or cyclohexyl.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein G₁ is C₃₋₇ cycloalkyl substituted with —NH₂. In aparticular embodiment, G₁ is cyclopropyl, cyclobutyl, cyclopropyl, orcyclohexyl, each of which is substituted with —NH₂.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein G₁ is 5-6 membered heterocycloalkenyl containing 1 doublebond, containing one to three heteroatoms independently selected from O,N, and S. In a particular embodiment, G₁ is dihydrofuranyl,dihydrothiazolyl, dihydrooxazolyl, dihydropyranyl, ordihydrothiopyranyl.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein G₁ is 5-6 membered heterocycloalkenyl containing 1 doublebond, containing one to three heteroatoms independently selected from O,N, and S, substituted with one or more independently selected R⁹, and R⁹is as previously defined. In another embodiment, G₁ is 5-6 memberedheterocycloalkenyl containing 1 double bond, containing one to threeheteroatoms independently selected from O, N, and S, substituted withone or two independently selected R⁹, and R⁹ is as previously defined.In a particular embodiment, G₁ is dihydrofuranyl, dihydrothiazolyl,dihydrooxazolyl, dihydropyranyl, or dihydrothiopyranyl, each of which issubstituted with one or two independently selected R⁹, and R⁹ is aspreviously defined.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein G₁ is 4-10 membered mono, bi or spirocyclicheterocycloalkyl containing one to three heteroatoms independentlyselected from O, N, and S. In a particular embodiment, G₁ is oxetanyl,azetidinyl, tetrahydrofuranyl, pyrolidinyl, tetrahydropyranyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or2,6-diaza-spiro[3.3]heptane.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein G₁ is 4-10 membered mono, bi or spirocyclicheterocycloalkyl containing one to three heteroatoms independentlyselected from O, N, and S, substituted with one or more independentlyselected R⁹, and R⁹ is as previously defined. In another embodiment, G₁is 4-10 membered mono, bi or spirocyclic heterocycloalkyl containing oneto three heteroatoms independently selected from O, N, and S,substituted with one or two independently selected R⁹, and R⁹ is aspreviously defined. In a particular embodiment, G₁ is oxetanyl,azetidinyl, tetrahydrofuranyl, pyrolidinyl, tetrahydropyranyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or2,6-diaza-spiro[3.3]heptanes, each of which is substituted with one ortwo independently selected R⁹, and R⁹ is as previously defined.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein R⁹ is oxo.

In another embodiment, a compound of the invention is according toFormula I-IVd, wherein R⁹ is R¹⁰.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein R¹⁰ is selected from OH, F, Cl, and —CN.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein R¹⁰ is C₁₋₄ alkyl. In a particular embodiment, R¹⁰ isselected from —CH₃, —CH₂—CH₃, and —CH(CH₃)₂. In a more particularembodiment, R¹⁰ is selected from —CH₃, and —CH₂—CH₃.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein R¹⁰ is C₁₋₄ alkyl substituted with one or moreindependently selected OH, halo, phenyl. In a further embodiment, R¹⁰ isC₁₋₄ alkyl substituted with one to three independently selected OH,halo, and phenyl.

In a more particular embodiment, R¹⁰ is —CH₃, —CH₂—CH₃, and —CH(CH₃)₂,each of which is substituted with one to three independently selectedOH, halo, and phenyl. In a most particular embodiment, R¹⁰ is —CF₃,—CH₂—CH₂—OH, and —CH₂-phenyl.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein R¹⁰ is C₁₋₄ alkoxy. In a particular embodiment, R¹⁰ isselected from —OCH₃, —OCH₂—CH₃, and —OC(CH₃)₃. In a particularembodiment, R¹⁰ is —OCH₃.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein R¹⁰ is selected from —SO₂CH₃, —C(═O)C₁₋₄ alkoxy, and—C(═O)C₁₋₄ alkyl. In a particular embodiment, R¹⁰ is selected from—SO₂CH₃, —C(═O)OCH₃, —C(═O)OCH₂CH₃, —C(═O)OCH(CH₃)₂, —C(═O)CH₃,—C(═O)CH₂CH₃, and —C(═O)OCH(CH₃)₂. In a most particular embodiment, R¹⁰is selected from —SO₂CH₃, —C(═O)OCH₃, and —C(═O)CH₃.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein R¹⁰ is —NR^(g)C(═O)C₁₋₄ alkyl, and R^(g) is as describedpreviously. In a particular embodiment, R¹⁰ is —NR^(g)C(═O)CH₃, or—NR^(g)C(═O)CH₂CH₃, and R^(g) is as described previously. In a moreparticular embodiment, R¹⁰ is —NR^(g)C(═O)CH₃, or —NR^(g)C(═O)CH₂CH₃,and R^(g) is H, —CH₃, or —CH₂CH₃. In a most particular embodiment, R¹⁰is —NHC(═O)CH₃, or —NHC(═O)CH₂CH₃.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein G₁ is 4-7 membered heterocycloalkyl containing one ormore heteroatoms independently selected from O, N, and S, each of whichis substituted with one or two independently selected R⁹ groups, and R⁹is oxo. In a further particular embodiment, G₁ is oxetanyl, azetidinyl,tetrahydrofuranyl, pyrolidinyl, tetrahydropyranyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, or2,6-diaza-spiro[3.3]heptane, each of which is substituted with one ortwo independently selected R⁹ groups, and R⁹ is oxo.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein G₁ is 4-7 membered heterocycloalkyl containing one ormore heteroatoms independently selected from O, N, and S, each of whichis substituted with one or two independently selected R⁹ groups, R⁹ isR¹⁰, and R¹⁰ is as previously described. In a further embodiment, G₁ isoxetanyl, azetidinyl, tetrahydrofuranyl, pyrolidinyl, tetrahydropyranyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or2,6-diaza-spiro[3.3]heptane, each of which is substituted with one ortwo independently selected R⁹ groups, R⁹ is R¹⁰, and R¹⁰ is aspreviously described. In a particular embodiment, R¹⁰ is selected fromOH, F, Cl, and —CN.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein G₁ is 4-7 membered heterocycloalkyl containing one ormore heteroatoms independently selected from O, N, and S, each of whichis substituted with one or two independently selected R⁹ groups, R⁹ isR¹⁰, and R¹⁰ is as previously described. In a further embodiment, G₁ isoxetanyl, azetidinyl, tetrahydrofuranyl, pyrolidinyl, tetrahydropyranyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or2,6-diaza-spiro[3.3]heptane, each of which is substituted with one ortwo independently selected R⁹ groups, R⁹ is R¹⁰, and R¹⁰ is aspreviously described. In a particular embodiment, R¹⁰ is selected C₁₋₄alkyl. In a more particular embodiment, R¹⁰ is selected from —CH₃,—CH₂—CH₃, and —CH(CH₃)₂. In a most particular embodiment, R¹⁰ isselected from —CH₃, and —CH₂—CH₃.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein G₁ is 4-7 membered heterocycloalkyl containing one ormore heteroatoms independently selected from O, N, and S, each of whichis substituted with one or two independently selected R⁹ groups, R⁹ isR¹⁰, and R¹⁰ is as previously described. In a further embodiment, G₁ isoxetanyl, azetidinyl, tetrahydrofuranyl, pyrolidinyl, tetrahydropyranyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or2,6-Diaza-spiro[3.3]heptane, each of which is substituted with one ortwo independently selected R⁹ groups, R⁹ is R¹⁰, and R¹⁰ is aspreviously described. In a particular embodiment, R¹⁰ is C₁₋₄ alkylsubstituted with one or more independently selected OH, halo, or phenyl.In a further embodiment, R¹⁰ is C₁₋₄ alkyl substituted with one to threeindependently selected OH, halo, or phenyl. In a more particularembodiment, R¹⁰ is —CH₃, —CH₂—CH₃, or —CH(CH₃)₂, each of which issubstituted with one to three independently selected OH, halo, orphenyl. In a most particular embodiment, R¹⁰ is —CF₃, —CH₂—CH₂—OH, or—CH₂-phenyl.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein G₁ is 4-7 membered heterocycloalkyl containing one ormore heteroatoms independently selected from O, N, and S, each of whichis substituted with one or two independently selected R⁹ groups, R⁹ isR¹⁰, and R¹⁰ is as previously described. In a further embodiment, G₁ isoxetanyl, azetidinyl, tetrahydrofuranyl, pyrolidinyl, tetrahydropyranyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or2,6-diaza-spiro[3.3]heptane, each of which is substituted with one ortwo independently selected R⁹ groups, R⁹ is R¹⁰, and R¹⁰ is aspreviously described. In a particular embodiment, R¹⁰ is C₁₋₄ alkoxy. Ina more particular embodiment, R¹⁰ is selected from —OCH₃, —OCH₂—CH₃, and—OC(CH₃)₃. In a most particular embodiment, R¹⁰ is —OCH₃.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein G₁ is 4-7 membered heterocycloalkyl containing one ormore heteroatoms independently selected from O, N, and S, each of whichis substituted with one or two independently selected R⁹ groups, R⁹ isR¹⁰, and R¹⁰ is as previously described. In a further embodiment, G₁ isoxetanyl, azetidinyl, tetrahydrofuranyl, pyrolidinyl, tetrahydropyranyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or2,6-Diaza-spiro[3.3]heptane, each of which is substituted with one ortwo independently selected R⁹ groups, R⁹ is R¹⁰, and R¹⁰ is aspreviously described. In a particular embodiment, R¹⁰ is selected from—SO₂CH₃, —C(═O)C₁₋₄alkoxy, and —C(═O)C₁₋₄ alkyl. In a more particularembodiment, R¹⁰ is selected from —SO₂CH₃, —C(═O)OCH₃, —C(═O)OCH₂CH₃,—C(═O)OCH(CH₃)₂, —C(═O)CH₃, —C(═O)CH₂CH₃, and —C(═O)OCH(CH₃)₂. In a mostparticular embodiment, R¹⁰ is selected from —SO₂CH₃, —C(═O)OCH₃, and—C(═O)CH₃.

In one embodiment, a compound of the invention is according to FormulaI-IVd, wherein G₁ is 4-7 membered heterocycloalkyl containing one ormore heteroatoms independently selected from O, N, and S, each of whichis substituted with one or two independently selected R⁹ groups, R⁹ isR¹⁰, and R¹⁰ is as previously described. In a further embodiment, G₁ isoxetanyl, azetidinyl, tetrahydrofuranyl, pyrolidinyl, tetrahydropyranyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or2,6-Diaza-spiro[3.3]heptane, each of which is substituted with one ortwo independently selected R⁹ groups, R⁹ is R¹⁰, and R¹⁰ is aspreviously described. In a particular embodiment, R¹⁰ is—NR^(g)C(═O)C₁₋₄ alkyl, and R^(g) is as described previously. In aparticular embodiment, R¹⁰ is —NR^(g)C(═O)CH₃, or —NR^(g)C(═O)CH₂CH₃,and R^(g) is as described previously. In a more particular embodiment,R¹⁰ is —NR^(g)C(═O)CH₃, or —NR^(g)C(═O)CH₂CH₃, and R^(g) is H, —CH₃, or—CH₂CH₃. In a most particular embodiment, R¹⁰ is —NHC(═O)CH₃, or—NHC(═O)CH₂CH₃.

In one embodiment, a compound of the invention is according to FormulaVa, Vb, Vc, or Vd:

wherein R^(6a), R^(6b), W₁, and G₁ are as described above.

In one embodiment, a compound of the invention is according to FormulaVa-Vd, wherein W₁ is C₁₋₄ alkylene. In a particular embodiment, W₁ is—CH₂—, —CH₂—CH₂—, —C(CH₃)H—, —CH₂—CH₂—CH₂— or —CH₂—C(CH₃)H—. In a moreparticular embodiment, W₁ is —CH₂—, or —C(CH₃)H—. In a most particularembodiment, W₁ is —CH₂—.

In one embodiment, a compound of the invention is according to FormulaVIa, VIb, VIc, or VId:

wherein R^(6a), R^(6b), and G₁ are as described above.

In one embodiment, a compound of the invention is according to FormulaVa-VId, wherein G₁ is 4-7 membered heterocycloalkyl containing one ormore heteroatoms independently selected from O, N, and S. In aparticular embodiment, G₁ is oxetanyl, azetidinyl, tetrahydrofuranyl,pyrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl,or thiomorpholinyl. In a more particular embodiment, G₁ is azetidinyl.

In one embodiment, a compound of the invention is according to FormulaVa-VId, wherein G₁ is 4-7 membered heterocycloalkyl containing one ormore heteroatoms independently selected from O, N, and S, whichheterocycle is substituted with one or more independently selected R⁹groups. In a further embodiment, G₁ is 4-7 membered heterocycloalkylcontaining one or more heteroatoms independently selected from O, N, andS, which heterocycle is substituted with one or two independentlyselected R⁹ groups. In a particular embodiment, G₁ is oxetanyl,azetidinyl, tetrahydrofuranyl, pyrolidinyl, tetrahydropyranyl,piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each of whichis substituted with one or two independently selected R⁹ groups. In amore particular embodiment, G₁ is azetidinyl substituted with one or twoindependently selected R⁹ groups.

In one embodiment, a compound of the invention is according to FormulaVa-VId, wherein G₁ is 4-7 membered heterocycloalkyl containing one ormore heteroatoms independently selected from O, N, and S, each of whichis substituted with one or two independently selected R⁹ groups, and R⁹is oxo. In a further particular embodiment, G₁ is oxetanyl, azetidinyl,tetrahydrofuranyl, pyrolidinyl, tetrahydropyranyl, piperidinyl,piperazinyl, morpholinyl, or thiomorpholinyl, each of which issubstituted with one or two independently selected R⁹ groups, and R⁹ isoxo.

In one embodiment, a compound of the invention is according to FormulaVa-VId, wherein G₁ is 4-7 membered heterocycloalkyl containing one ormore heteroatoms independently selected from O, N, and S, each of whichis substituted with one or two independently selected R⁹ groups, R⁹ isR¹⁰, and R¹⁰ is as previously described. In a further embodiment, G₁ isoxetanyl, azetidinyl, tetrahydrofuranyl, pyrolidinyl, tetrahydropyranyl,piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each of whichis substituted with one or two independently selected R⁹ groups, R⁹ isR¹⁰, and R¹⁰ is as previously described. In a particular embodiment, R¹⁰is selected from OH, F, Cl, and —CN. In a more particular embodiment, G₁is azetidinyl substituted with one or two independently selected R⁹groups, R⁹ is R¹⁰, and R¹⁰ is as previously described. In a mostparticular embodiment, R¹⁰ is selected from OH, F, Cl, and —CN.

In one embodiment, a compound of the invention is according to FormulaVa-VId, wherein G₁ is 4-7 membered heterocycloalkyl containing one ormore heteroatoms independently selected from O, N, and S, each of whichis substituted with one or two independently selected R⁹ groups, R⁹ isR¹⁰, and R¹⁰ is as previously described. In a further embodiment, G₁ isoxetanyl, azetidinyl, tetrahydrofuranyl, pyrolidinyl, tetrahydropyranyl,piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each of whichis substituted with one or two independently selected R⁹ groups, R⁹ isR¹⁰, and R¹⁰ is as previously described. In a particular embodiment, R¹⁰is selected C₁₋₄ alkyl. In a more particular embodiment, R¹⁰ is selectedfrom —CH₃, —CH₂—CH₃, and —CH(CH₃)₂. In a most particular embodiment, R¹⁰is selected from —CH₃, and —CH₂—CH₃.

In one embodiment, a compound of the invention is according to FormulaVa-VId, wherein G₁ is 4-7 membered heterocycloalkyl containing one ormore heteroatoms independently selected from O, N, and S, each of whichis substituted with one or two independently selected R⁹ groups, R⁹ isR¹⁰, and R¹⁰ is as previously described. In a further embodiment, G₁ isoxetanyl, azetidinyl, tetrahydrofuranyl, pyrolidinyl, tetrahydropyranyl,piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each of whichis substituted with one or two independently selected R⁹ groups, R⁹ isR¹⁰, and R¹⁰ is as previously described. In a particular embodiment, R¹⁰is C₁₋₄ alkyl substituted with one or more independently selected OH,halo, phenyl. In a further embodiment, R¹⁰ is C₁₋₄ alkyl substitutedwith one to three independently selected OH, halo, and phenyl. In a moreparticular embodiment, R¹⁰ is —CH₃, —CH₂—CH₃, and —CH(CH₃)₂, each ofwhich is substituted with one to three independently selected OH, halo,and phenyl. In a most particular embodiment, R¹⁰ is —CF₃, —CH₂—CH₂—OH,and —CH₂-phenyl.

In one embodiment, a compound of the invention is according to FormulaVa-VId, wherein G₁ is 4-7 membered heterocycloalkyl containing one ormore heteroatoms independently selected from O, N, and S, each of whichis substituted with one or two independently selected R⁹ groups, R⁹ isR¹⁰, and R¹⁰ is as previously described. In a further embodiment, G₁ isoxetanyl, azetidinyl, tetrahydrofuranyl, pyrolidinyl, tetrahydropyranyl,piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each of whichis substituted with one or two independently selected R⁹ groups, R⁹ isR¹⁰, and R¹⁰ is as previously described. In a particular embodiment, R¹⁰is C₁₋₄ alkoxy. In a more particular embodiment, R¹⁰ is selected from—OCH₃, —OCH₂—CH₃, and —OC(CH₃)₃. In a most particular embodiment, R¹⁰ is—OCH₃.

In one embodiment, a compound of the invention is according to FormulaVa-VId, wherein G₁ is 4-7 membered heterocycloalkyl containing one ormore heteroatoms independently selected from O, N, and S, each of whichis substituted with one or two independently selected R⁹ groups, R⁹ isR¹⁰, and R¹⁰ is as previously described. In a further embodiment, G₁ isoxetanyl, azetidinyl, tetrahydrofuranyl, pyrolidinyl, tetrahydropyranyl,piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each of whichis substituted with one or two independently selected R⁹ groups, R⁹ isR¹⁰, and R¹⁰ is as previously described. In a particular embodiment, R¹⁰is selected from —SO₂CH₃, —C(═O)C₁₋₄ alkoxy, and —C(═O)C₁₋₄ alkyl. In amore particular embodiment, R¹⁰ is selected from —SO₂CH₃, —C(═O)OCH₃,—C(═O)OCH₂CH₃, —C(═O)OCH(CH₃)₂, —C(═O)CH₃, —C(═O)CH₂CH₃, and—C(═O)OCH(CH₃)₂. In a most particular embodiment, R¹⁰ is selected from—SO₂CH₃, —C(═O)OCH₃, and —C(═O)CH₃.

In one embodiment, a compound of the invention is according to FormulaVa-VId, wherein G₁ is 4-7 membered heterocycloalkyl containing one ormore heteroatoms independently selected from O, N, and S, each of whichis substituted with one or two independently selected R⁹ groups, R⁹ isR¹⁰, and R¹⁰ is as previously described. In a further embodiment, G₁ isoxetanyl, azetidinyl, tetrahydrofuranyl, pyrolidinyl, tetrahydropyranyl,piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each of whichis substituted with one or two independently selected R⁹ groups, R⁹ isR¹⁰, and R¹⁰ is as previously described. In a particular embodiment, R¹⁰is —NR^(g)C(═O)C₁₋₄ alkyl, and R^(g) is as described previously. In aparticular embodiment, R¹⁰ is —NR^(g)C(═O)CH₃, or —NR^(g)C(═O)CH₂CH₃,and R^(g) is as described previously. In a more particular embodiment,R¹⁰ is —NR^(g)C(═O)CH₃, or —NR^(g)C(═O)CH₂CH₃, and R^(g) is H, —CH₃, or—CH₂CH₃. In a most particular embodiment, R¹⁰ is —NHC(═O)CH₃, or—NHC(═O)CH₂CH₃.

In one embodiment, a compound of the invention is according to FormulaI-VId, wherein R^(6a) is H, —CH₃ or halo, and R^(6b) is H. In aparticular embodiment, R^(6a) is H, —CH₃, F, or Cl, and R^(6b) is H. Ina more particular embodiment, R^(6a) is H, —CH₃, or F, and R^(6b) is H.

In one embodiment, a compound of the invention is according to FormulaI-VId, wherein R^(6a) is H, and R^(6b) is H, —CH₃ or halo. In aparticular embodiment, R^(6a) is H, and R^(6b) is H, —CH₃, F, or Cl. Ina more particular embodiment, R^(6a) is H, and R^(6b) is H, —CH₃, or F.

In another embodiment, R^(6a) and R^(6b) are both H.

In one embodiment, a compound of the invention according to Formula I isselected from:

-   2-((2-ethyl-8-methyl-6-(piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,-   2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,-   2-((2-ethyl-6-(4-(2-(3-hydroxy-3-methylazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,-   (R)-2-((2-ethyl-6-(4-(2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl)piperazin-1-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,-   (S)-2-((2-ethyl-6-(4-(2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl)piperazin-1-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,-   2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-3,3-dimethylpiperazin-1-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-8-methylimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone,-   (R)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-8-methylimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-(3-hydroxypyrrolidin-1-yl)ethanone,-   (S)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-8-methylimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-(3-hydroxypyrrolidin-1-yl)ethanone,-   2-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,-   2-(ethyl(2-ethyl-8-methyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,-   2-((2-ethyl-8-fluoro-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,-   2-(4-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethyl-8-fluoroimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-N-methylacetamide,-   2-(4-(2-ethyl-8-fluoro-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone,-   (S)-2-(4-(2-ethyl-8-fluoro-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-(3-hydroxypyrrolidin-1-yl)ethanone,-   (R)-2-(4-(2-ethyl-8-fluoro-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-(3-hydroxypyrrolidin-1-yl)ethanone,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-7-methylimidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone,-   2-[(2-Ethyl-7-fluoro-6-{4-[2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-imidazo[1,2-a]pyridin-3-yl)-methyl-amino]-4-(4-fluoro-phenyl)-thiazole-5-carbonitrile,-   2-[4-(2-Ethyl-7-fluoro-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-a]pyridin-6-yl)-piperazin-1-yl]-1-(3-hydroxy-azetidin-1-yl)-ethanone,-   2-[4-(2-Ethyl-7-fluoro-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-a]pyridin-6-yl)-piperazin-1-yl]-1-(3-hydroxy-pyrrolidin-1-yl)-ethanone,-   2-[4-(2-Ethyl-7-fluoro-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-a]pyridin-6-yl)-piperazin-1-yl]-1-(3-hydroxy-pyrrolidin-1-yl)-ethanone,-   2-(4-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-N-methylacetamide,-   tert-butyl    4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazine-1-carboxylate,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone,-   (S)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-(3-hydroxypyrrolidin-1-yl)ethanone,-   (R)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-(3-hydroxypyrrolidin-1-yl)ethanone,-   N-(1-(2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)acetoyl)pyrrolidin-3-yl)acetamide,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-(3-fluoroazetidin-1-yl)ethanone,-   1-(3,3-difluoroazetidin-1-yl)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)ethanone,-   1-(azetidin-1-yl)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)ethanone,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-(pyrrolidin-1-yl)ethanone,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-morpholinoethanone,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)acetamide,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-(3-(hydroxymethyl)azetidin-1-yl)ethanone,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-N,N-dimethylacetamide,-   ethyl    2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)acetate,-   ethyl    2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)propanoate,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)acetonitrile,-   N-(6-(4-((1-cyclopropyl-1H-tetrazol-5-yl)methyl)piperazin-1-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,-   N-(2-ethyl-6-(4-(oxazol-2-ylmethyl)piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,-   N-(6-(4-((1,2,4-oxadiazol-3-yl)methyl)piperazin-1-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)acetic    acid,-   2-hydroxyethyl    4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazine-1-carboxylate,-   tert-butyl    2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate,-   tert-butyl    3-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate,-   (4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)(pyrrolidin-2-yl)methanone,-   (4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)(pyrrolidin-3-yl)methanone,-   1-(3-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazine-1-carbonyl)pyrrolidin-1-yl)ethanone,-   (4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)(1-(methylsulfonyl)pyrrolidin-3-yl)methanone,-   1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-2-hydroxyethanone,-   1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)propan-1-one,-   1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-4-hydroxybutan-1-one,-   4-(dimethylamino)-1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)butan-1-one,-   N-(2-ethyl-6-(4-(methylsulfonyl)piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,-   N-(6-(4-(3-chloropropylsulfonyl)piperazin-1-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,-   N-(6-(4-(3-(dimethylamino)propylsulfonyl)piperazin-1-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,-   N-(2-ethyl-6-(4-(3-(pyrrolidin-1-yl)propylsulfonyl)piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,-   3-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-ylsulfonyl)propan-1-ol,-   methyl    2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-ylsulfonyl)acetate,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-ylsulfonyl)acetic    acid,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-ylsulfonyl)acetamide,-   tert-butyl    4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-3-oxopiperazine-1-carboxylate,-   tert-butyl    4-(3-((4-(4-chlorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)-3-oxopiperazine-1-carboxylate,-   ethyl    2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-3-oxopiperazin-1-yl)acetate,-   1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-4-(methylsulfonyl)piperazin-2-one,-   N-(2-ethyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,-   N-(6-(1-(chloromethylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,-   4-(4-chlorophenyl)-N-(2-ethyl-6-(1-(methylsulfonyl)-2,5-dihydro-1H-pyrrol-3-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylthiazol-2-amine,-   4-(4-chlorophenyl)-N-(2-ethyl-6-(1-(methylsulfonyl)-1,4,5,6-tetrahydropyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylthiazol-2-amine,-   4-(4-tert-butylphenyl)-N-(2-ethyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylthiazol-2-amine,-   N-(2-ethyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-methoxyphenyl)-N-methylthiazol-2-amine,-   N-(2-ethyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-methyl-4-(4-(trifluoromethoxy)phenyl)thiazol-2-amine,-   4-(3,4-difluorophenyl)-N-(2-ethyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylthiazol-2-amine,-   3-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-5,6-dihydropyridin-1    (2H)-ylsulfonyl)propyl acetate,-   3-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-5,6-dihydropyridin-1    (2H)-ylsulfonyl)propan-1-ol,-   4-(2-ethyl-3-((4-(4-chlorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-3,6-dihydro-2H-thiopyran    1,1-dioxide,-   N-(2-ethyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)-5-fluoro-4-(4-fluorophenyl)-N-methylthiazol-2-amine,-   tert-butyl    4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-3-hydroxypiperidine-1-carboxylate,-   4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-1-(methylsulfonyl)piperidin-3-ol,-   N-(2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,-   4-(4-tert-butylphenyl)-N-(2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylthiazol-2-amine,-   N-(2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-methoxyphenyl)-N-methylthiazol-2-amine,-   4-(3,4-difluorophenyl)-N-(2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylthiazol-2-amine,-   N-(2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-methyl-4-(4-(trifluoromethyl)phenyl)thiazol-2-amine,-   N-(2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-methyl-4-(4-(trifluoromethoxy)phenyl)thiazol-2-amine,-   N-(6-(1-(3-chloropropylsulfonyl)piperidin-4-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,-   N-(6-(1-(3-(dimethylamino)propylsulfonyl)piperidin-4-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,-   N-(2-ethyl-6-(1-(3-morpholinopropylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,-   N-(2-ethyl-6-(1-(3-(pyrrolidin-1-yl)propylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,-   N-(6-(1-(3-aminopropylsulfonyl)piperidin-4-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,-   N-(2-ethyl-6-(1-(2-morpholinoethylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,-   4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidine-1-sulfonamide,-   3-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-ylsulfonyl)propyl    acetate,-   3-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-ylsulfonyl)propan-1-ol,-   3-(4-(2-ethyl-3-((5-fluoro-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-ylsulfonyl)propan-1-ol,-   2-(2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorobenzonitrile,-   2-(2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-5-methylthiazol-4-yl)-5-fluorobenzonitrile,-   N-(2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluoro-2-methylphenyl)-N-methylthiazol-2-amine,-   4-(2-chloro-4-fluorophenyl)-N-(2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylthiazol-2-amine,-   4-(2,4-difluorophenyl)-N-(2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylthiazol-2-amine,-   N-(2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N,5-dimethylthiazol-2-amine,-   4-(4-fluorophenyl)-N-(2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(d3-methyl)thiazol-2-amine,-   4-(4-fluorophenyl)-N-(2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(d3-methyl)-(d-thiazol-2)-amine,-   methyl    2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carboxylate,-   1-(2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazol-5-yl)ethanone,-   N-(2-(2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorophenyl)acetamide,-   (2-(2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorophenyl)methanol,-   ethyl    2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-5,6-dihydropyridin-1    (2H)-yl)acetate,-   ethyl    2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)acetate,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone,-   (R)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-1-(3-hydroxypyrrolidin-1-yl)ethanone,-   (S)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-1-(3-hydroxypyrrolidin-1-yl)ethanone,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-1-(3-(hydroxymethyl)azetidin-1-yl)ethanone,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-N,N-dimethylacetamide,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-1-(pyrrolidin-1-yl)ethanone,-   (S)-1-(2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)acetoyl)pyrrolidine-3-carbonitrile,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-1-(3-(hydroxymethyl)pyrrolidin-1-yl)ethanone,-   4-((4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)methyl)-1,3-dioxolan-2-one,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-N-(2-hydroxyethyl)-N-methylacetamide,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-N-methoxy-N-methylacetamide,-   N-(cyanomethyl)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-N-methylacetamide,-   5-((4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)methyl)oxazolidin-2-one,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-N-(3-hydroxypropyl)acetamide,-   1-(3,3-difluoroazetidin-1-yl)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)ethanone,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)acetamide,-   1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-2-(pyrrolidin-1-yl)ethanone,-   1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-2-(methylamino)ethanone,-   1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-2-(3-hydroxyazetidin-1-yl)ethanone,-   2-(dimethylamino)-1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)ethanone,-   3-(dimethylamino)-1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)propan-1-one,-   2-(3,3-difluoroazetidin-1-yl)-1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)ethanone,-   1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-3-(methylamino)propan-1-one,-   1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-2-(3-fluoroazetidin-1-yl)ethanone,-   1-(3-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)azetidin-1-yl)ethanone,-   5-bromo-N-(2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,-   2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,-   2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carboxamide,-   2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,-   2-((2-ethyl-6-(4-(2-(3-(hydroxymethyl)azetidin-1-yl)-2-oxoethyl)piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,-   2-(4-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-N,N-dimethylacetamide,-   2-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,-   (R)-2-((2-ethyl-6-(1-(2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,-   (S)-2-((2-ethyl-6-(1-(2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,-   2-((2-ethyl-6-(1-(2-(3-(hydroxymethyl)azetidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,-   2-(4-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-N,N-dimethylacetamide,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-(3-(hydroxymethyl)azetidin-1-yl)ethanone,-   (2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazol-5-yl)methanol,-   (2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methanol,-   (2-((6-(1-(3-(dimethylamino)propylsulfonyl)piperidin-4-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazol-5-yl),-   (2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-(trifluoromethyl)phenyl)thiazol-5-yl)methanol,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-1-(pyrrolidin-1-yl)ethanone,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-1-(3-(hydroxymethyl)azetidin-1-yl)ethanone,-   2-(dimethylamino)-1-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)ethanone,-   1-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)propan-1-one,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-N,N-dimethylacetamide,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-N,N-dimethylacetamide,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(2,2,2-trifluoroacetoyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-N,N-dimethylacetamide,-   1-(2-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazol-5-yl)-2,2,2-trifluoroethanone,-   1-(2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazol-5-yl)-2,2,2-trifluoroethanone,-   2-(2-((2-ethyl-6-(piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-5-methylthiazol-4-yl)-5-fluorobenzonitrile,-   2-(2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-5-methylthiazol-4-yl)-5-fluorobenzonitrile,-   2-(4-(3-((4-(2-cyano-4-fluorophenyl)-5-methylthiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-N-methylacetamide,-   2-(2-((2-ethyl-6-(4-(2-(3-fluoroazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorobenzonitrile,-   2-(2-((6-(4-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorobenzonitrile,-   2-(2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorobenzonitrile,-   2-(2-((6-(4-(2-(azetidin-1-yl)-2-oxoethyl)piperazin-1-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorobenzonitrile,-   2-(4-(3-((4-(2-cyano-4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-N,N-dimethylacetamide,-   2-(4-(3-((4-(2-cyano-4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-N-methylacetamide,-   2-(2-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorobenzonitrile,-   2-(4-(3-((4-(2-cyano-4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-N,N-dimethylacetamide,-   2-(2-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-5-methylthiazol-4-yl)-5-fluorobenzonitrile,-   2-(5-((2-ethyl-6-(I-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-1,2,4-thiadiazol-3-yl)-5-fluorobenzonitrile,-   2-(4-(2-(2-cyanoethyl)-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-N,N-dimethylacetamide,-   3-(3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)amino)-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-2-yl)propanenitrile,-   3-(6-(1-(2-(dimethylamino)-2-oxoethyl)piperidin-4-yl)-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-2-yl)propanamide,-   N-(6-(3-aminoazetidin-1-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,-   2-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)azetidin-3-ylamino)-1-(3-hydroxyazetidin-1-yl)ethanone,-   N-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)azetidin-3-yl)-2-(3-hydroxyazetidin-1-yl)acetamide,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)ethanol,-   N-(2-ethyl-6-morpholinoimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,-   4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-thiomorpholine-   1,1-dioxide,-   1-(3-((4-(4-chlorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)imidazolidin-2-one,-   ethyl    2-(3-(3-((4-(4-chlorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)-2-oxoimidazolidin-1-yl)acetate,-   4-(4-chlorophenyl)-N-methyl-N-(6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-3-yl)thiazol-2-amine,-   2-(2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazol-5-yl)acetonitrile,-   2-ethyl-N-(4-(4-fluorophenyl)pyrimidin-2-yl)-N-methyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-amine,-   3-(4-chlorophenyl)-N-(2-ethyl-6-(4-(methylsulfonyl)piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)-N-methyl-1,2,4-thiadiazol-5-amine,-   N-(2-ethyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)-3-(4-fluorophenyl)-N-methyl-1,2,4-oxadiazol-5-amine,-   2-(4-(2-ethyl-3-((3-(4-fluorophenyl)-1,2,4-thiadiazol-5-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-5,6-dihydropyridin-1(2H)-yl)-N,N-dimethylacetamide,-   2-(4-(2-ethyl-3-((3-(4-fluorophenyl)-1,2,4-thiadiazol-5-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-N,N-dimethylacetamide,-   N-(6-(4-((1H-imidazol-5-yl)methyl)piperazin-1-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,-   N-(2-ethyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-methyl-4-(4-(trifluoromethyl)phenyl)thiazol-2-amine,-   N-cyclopropyl-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)acetamide,-   5-((4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)methyl)-3-methyloxazolidin-2-one,-   (R)-5-((4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)methyl)oxazolidin-2-one,-   (S)-5-((4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)methyl)oxazolidin-2-one,-   4-((4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)methyl)oxazolidin-2-one,-   N-(2-ethyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)-3-(4-fluorophenyl)-N-methyl-1,2,4-thiadiazol-5-amine,-   1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)propane-1,2-dione,-   5-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazine-1-carbonyl)pyrrolidin-2-one,-   (1-aminocyclopropyl)(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)methanone,-   (S)-1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-2-hydroxypropan-1-one,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-2-oxoacetamide,-   1-benzyl-4-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazine-1-carbonyl)pyrrolidin-2-one,-   3-(3-((4-(4-chlorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)oxazolidin-2-one,-   2-(2-ethyl-3-((4-(4-chlorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-1-[1,2]thiazinane-1,1-dioxide,-   4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-N-(thiophen-2-yl)-5,6-dihydropyridine-1(2H)-carboxamide,-   4-(4-chlorophenyl)-N-(2-ethyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylthiazol-2-amine,-   4-(4-chlorophenyl)-N-(2-ethyl-6-(1-(trifluoromethylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylthiazol-2-amine,-   1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-4-ol,-   2-(4-(3-((4-(4-chlorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)ethanol,-   4-(2-ethyl-3-((4-(4-chlorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-thiomorpholine-1,1-dioxide,-   tert-butyl    4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-5,6-dihydropyridine-1    (2H)-carboxylate,-   1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)propan-1-one,-   N-(2-ethyl-6-(piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,-   N-(6-(1-benzylpiperidin-4-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,-   N-(2-ethyl-6-(1-isopropylpiperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,-   tert-butyl    4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidine-1-carboxylate,-   N-(6-(3,6-dihydro-2H-pyran-4-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,-   4-(4-chlorophenyl)-N-(6-(3,6-dihydro-2H-pyran-4-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-N-methylthiazol-2-amine,-   (2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-4,5-dihydrooxazol-5-yl)methanol,-   2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-1-(3-hydroxypyrrolidin-1-yl)ethanone,-   2-(2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorophenol,-   tert-butyl    4-(3-((3-(4-chlorophenyl)-1,2,4-thiadiazol-5-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)piperazine-1-carboxylate,-   N-(6-(4-((1H-imidazol-2-yl)methyl)piperazin-1-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,-   cyclopropyl(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)methanone,-   ethyl    2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-2-oxoacetate,-   [6-(1,1-Dioxo-isothiazolidin-2-yl)-2-ethyl-imidazo[1,2-a]pyridin-3-yl]-[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amine,-   tert-butyl    4-(3-((4-(4-chlorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)-5,6-dihydropyridine-1    (2H)-carboxylate,-   4-(4-chlorophenyl)-N-(6-(3,6-dihydro-2H-thiopyran-4-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-N-methylthiazol-2-amine,-   N-(6-(4,4-difluoropiperidin-1-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,-   N-(6-(1-(3-chloropropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,-   tert-butyl    4-(3-((4-(4-chlorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)piperazine-1-carboxylate,-   N-(6-(1-(cyclohexylmethyl)piperidin-4-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,-   N-(2-ethyl-6-(5-methyl-4,5-dihydrooxazol-2-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,-   N-(2-ethyl-6-(4-methyl-4,5-dihydrooxazol-2-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,-   2-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-4,5-dihydrooxazole-4-carboxylic    acid,-   (2-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-4,5-dihydrooxazol-4-yl)methanol,    and-   4-(4-chlorophenyl)-N-(6-(4,5-dihydrooxazol-2-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-N-methylthiazol-2-amine.

In one embodiment, a compound of the invention according to Formula I is2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile.

In another embodiment, a compound of the invention according to FormulaI is not2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile.

In one embodiment a compound of the invention is not an isotopicvariant.

In one aspect a compound of the invention according to any one of theembodiments herein described is present as the free base.

In one aspect a compound of the invention according to any one of theembodiments herein described is a pharmaceutically acceptable salt.

In one aspect a compound of the invention according to any one of theembodiments herein described is a solvate of the compound.

In one aspect a compound of the invention according to any one of theembodiments herein described is a solvate of a pharmaceuticallyacceptable salt of a compound.

While specified groups for each embodiment have generally been listedabove separately, a compound of the invention includes one in whichseveral or each embodiment in the above Formula, as well as otherformulae presented herein, is selected from one or more of particularmembers or groups designated respectively, for each variable. Therefore,this invention is intended to include all combinations of suchembodiments within its scope.

While specified groups for each embodiment have generally been listedabove separately, a compound of the invention may be one for which oneor more variables (for example, R groups) is selected from one or moreembodiments according to any of the Formula(e) listed above. Therefore,the present invention is intended to include all combinations ofvariables from any of the disclosed embodiments within its scope.

Alternatively, the exclusion of one or more of the specified variablesfrom a group or an embodiment, or combinations thereof is alsocontemplated by the present invention.

In certain aspects, the present invention provides prodrugs andderivatives of the compounds according to the formulae above. Prodrugsare derivatives of the compounds of the invention, which havemetabolically cleavable groups and become by solvolysis or underphysiological conditions the compounds of the invention, which arepharmaceutically active, in vivo. Such examples include, but are notlimited to, choline ester derivatives and the like, N-alkylmorpholineesters and the like.

Other derivatives of the compounds of this invention have activity inboth their acid and acid derivative forms, but the acid sensitive formoften offers advantages of solubility, tissue compatibility, or delayedrelease in the mammalian organism (Bundgard, H, 1985). Prodrugs includeacid derivatives well know to practitioners of the art, such as, forexample, esters prepared by reaction of the parent acid with a suitablealcohol, or amides prepared by reaction of the parent acid compound witha substituted or unsubstituted amine, or acid anhydrides, or mixedanhydrides. Simple aliphatic or aromatic esters, amides and anhydridesderived from acidic groups pendant on the compounds of this inventionare preferred prodrugs. In some cases it is desirable to prepare doubleester type prodrugs such as (acyloxy)alkyl esters or((alkoxycarbonyl)oxy)alkylesters. Particularly useful are the C₁ to C₈alkyl, C₂-C₈ alkenyl, aryl, C₇-C₁₂ substituted aryl, and C₇-C₁₂arylalkyl esters of the compounds of the invention.

CLAUSES

-   1) A compound according to Formula I:

-   -   wherein    -   R^(1a) is H, halo or C₁₋₄ alkyl;    -   R^(1b) is:        -   halo,        -   C₁₋₄ alkyl (which alkyl is optionally substituted with one            or more independently selected halo), or        -   C₁₋₄ alkoxy (which alkoxy is optionally substituted with one            or more independently selected halo);    -   X is —S—, —O—, —N═CH—, —CH═N— or —CH═CH—;    -   W is N, or CR³    -   when W is N, R² is:        -   H,        -   —CN,        -   halo,        -   C₁₋₄ alkyl (which alkyl is optionally substituted with one            or more independently selected OH, or CN)        -   —C(═O)CH₃,        -   —C(═O)CF₃,        -   —C(═O)OCH₃,        -   —C(═O)NH₂,        -   —NHC(═O)CH₃, or    -   when W is CR³, one of R² or R³ is:        -   H,        -   —CN,        -   halo,        -   C₁₋₄ alkyl (which alkyl is optionally substituted with one            or more independently selected OH, or CN)        -   —C(═O)CH₃,        -   —C(═O)CF₃,        -   —C(═O)OCH₃,        -   —C(═O)NH₂,        -   —NHC(═O)CH₃,    -   and the other is H, or C₁₋₄ alkyl;    -   R⁴ is C₁₋₄ alkyl;    -   R⁵ is C₁₋₄ alkyl optionally substituted with one or more        independently selected CN, OH, halo, or —C(═O)NH₂;    -   one of R^(6a) or R^(6b) is selected from H, —CH₃, and halo, and        the other is H;    -   Cy is:        -   C₄₋₁₀ cycloalkyl,        -   4-10 membered mono or bicyclic heterocycloalkyl containing            one or more heteroatoms independently selected from O, N,            and S, or        -   4-7 membered heterocycloalkenyl containing 1 double bond,            containing one or more heteroatoms independently selected            from O, N, and S;    -   each R⁷ is independently selected from:        -   OH,        -   oxo,        -   halo, and        -   C₁₋₄ alkyl (which alkyl is optionally substituted with one            or more independently selected OH, or C₁₋₄ alkoxy);    -   the subscript a is 0, 1 or 2;    -   R⁸ is -(L₁-W₁)_(m)-L₂-G₁,    -   wherein        -   L₁ is absent, or is —O—, —C(═O)—, —NR, —NR^(h)C(═O)—, or            —SO₂—;        -   W₁ is C₁₋₄ alkylene;        -   the subscript m is 0, or 1;        -   L₂ is absent, or is —O—, —C(═O)—, —C(═O)O—, —OC(═O)—,            —C(═O)—C(═O)—, —C(═O)—C(═O)NR^(a)—, —NR^(b)—, —C(═O)NR^(e)—,            —NR^(d)C(═O)—, —NR^(j)C(═O)O—, —SO₂—, —SO₂NR^(e)— or            —NR^(f)SO₂—;        -   G₁ is            -   H,            -   —CN,            -   C₁₋₄ alkyl (which alkyl is optionally substituted with                one or more independently selected —CN, OH, halo or                phenyl),            -   C₃₋₇ cycloalkyl (which cycloalkyl is optionally                substituted with —NH₂),            -   5-6 membered heterocycloalkenyl containing 1 double bond                containing one or more heteroatoms independently                selected from O, N, and S (which heterocycloalkenyl is                optionally substituted with one or more independently                selected R⁹ groups),            -   4-10 membered mono, bi or spirocyclic heterocycloalkyl                containing one or more heteroatoms independently                selected from O, N, and S (which heterocycloalkyl is                optionally substituted with one or more independently                selected R⁹ groups), or            -   5-6 membered heteroaryl containing one or more                heteroatoms independently selected from O, N, and S                (which heteroaryl is optionally substituted with one or                more independently selected R¹⁰ groups),    -   each R⁹ is oxo, or R¹⁰;    -   each R¹⁰ is:        -   —OH,        -   halo,        -   —CN,        -   C₁₋₄ alkyl (which alkyl is optionally substituted with one            or more independently selected OH, halo, or phenyl),        -   C₁₋₄ alkoxy,        -   C₃₋₇ cycloalkyl,        -   phenyl,        -   —SO₂CH₃,        -   —C(═O)C₁₋₄ alkoxy,        -   —C(═O)C₁₋₄ alkyl, or        -   —NR^(g)C(═O)C₁₋₄ alkyl; and    -   each R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), R^(h),        R^(i), and R^(j) is independently selected from H and C₁₋₄        alkyl; or a pharmaceutically acceptable salt, or a solvate, or a        pharmaceutically acceptable salt of a solvate thereof; or a        biologically active metabolite thereof.

-   2) A compound or pharmaceutically acceptable salt thereof, according    to clause 1, wherein R^(1a) is F, Cl, —CH₃ or —C₂H₅.

-   3) A compound or pharmaceutically acceptable salt thereof, according    to clause 1, wherein R^(1a) is H.

-   4) A compound or pharmaceutically acceptable salt thereof, according    to any one of clauses 1-3, wherein R^(1b) is F, Cl, —CH₃, —C₂H₅,    —CF₃, —OCH₃, or —OCF₃.

-   5) A compound or pharmaceutically acceptable salt thereof, according    to any one of clauses 1-3, wherein R^(1b) is F.

-   6) A compound or pharmaceutically acceptable salt thereof, according    to any one of clauses 1-5, wherein X is —S— or —O—.

-   7) A compound or pharmaceutically acceptable salt thereof, according    to any one of clauses 1-5, wherein X is —S—.

-   8) A compound or pharmaceutically acceptable salt thereof, according    to any one of clauses 1-5, wherein W is N.

-   9) A compound or pharmaceutically acceptable salt thereof, according    to any one of clauses 1-5, wherein W is CR³.

-   10) A compound or pharmaceutically acceptable salt thereof,    according to clause 9, wherein R³ is H, CN, F, or Cl.

-   11) A compound or pharmaceutically acceptable salt thereof,    according to clause 1, wherein the compound is according to Formula    II:

-   -   wherein R⁴, R⁵, R^(6a), R^(6b), R⁷, R⁸ and the subscript a are        according to clause 1.

-   12) A compound or pharmaceutically acceptable salt thereof,    according to clause 1, wherein the compound is according to Formula    III:

-   -   wherein R⁴, R⁵, R^(6a), R^(6b), R⁷, R⁸ and the subscript a are        according to clause 1.

-   13) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-12, wherein R⁴ is —CH₃, or —C₂H₅.

-   14) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-12, wherein R⁴ is —CH₃.

-   15) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-14, wherein R⁵ is C₁₋₄ alkyl.

-   16) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-14, wherein R⁵ is —CH₃, or —C₂H₅.

-   17) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-14, wherein R⁵ is C₁₋₄ alkyl    substituted with one CN, OH, halo, or —C(═O)NH₂.

-   18) A compound or pharmaceutically acceptable salt thereof,    according to clause 17, wherein R⁵ is —CH₃, —C₂H₅ or —C₃H₇    substituted with one CN, OH, halo, or —C(═O)NH₂.

-   19) A compound or pharmaceutically acceptable salt thereof,    according to clause 17, wherein R⁵ is —CH₂—CH₂—CN, —CH₂—CH₂—OH,    —CH₂—CF₃, or —CH₂—CH₂—C(═O)NH₂.

-   20) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-19, wherein Cy is C₄₋₁₀    cycloalkyl.

-   21) A compound or pharmaceutically acceptable salt thereof,    according to clause 20, wherein Cy is cyclobutyl, cyclopentyl or    cyclohexyl.

-   22) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-19, wherein Cy is 4-10 membered    mono or bicyclic heterocycloalkyl containing one or more heteroatoms    independently selected from O, N, and S.

-   23) A compound or pharmaceutically acceptable salt thereof,    according to clause 22, wherein Cy is oxetanyl, azetidinyl,    tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl,    piperazinyl, morpholinyl, or thiomorpholinyl.

-   24) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-19, wherein Cy is 4-7 membered    heterocycloalkenyl containing 1 double bond, containing one or more    heteroatoms independently selected from O, N, and S.

-   25) A compound or pharmaceutically acceptable salt thereof,    according to clause 24, wherein Cy is dihydrofuranyl,    dihydrothiazolyl, dihydrooxazolyl, dihydropyranyl,    tetrahydropyridinyl, or dihydrothiopyranyl.

-   26) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-25, wherein the subscript a is 1    or 2, and R⁷ is OH, oxo, F, Cl, or —CH₃.

-   27) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-25, wherein the subscript a is 0.

-   28) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-27, wherein R⁸ is    -(L₁-W₁)_(m)-L₂-G₁.

-   29) A compound according to Formula I, II, or III, wherein the    compound is according to Formula IVa, IVb, IVc or IVd:

-   -   wherein R^(6a), R^(6b), L₁, W₁, L₂, G₁ and the subscript m are        according to clause 1.

-   30) A compound or pharmaceutically acceptable salt thereof,    according to clause 28, or 29, wherein the subscript m is 1, L₁ is    absent.

-   31) A compound or pharmaceutically acceptable salt thereof,    according to clause 28, or 29, wherein the subscript m is 1, L₁ is    —C(═O)—, or —SO₂—.

-   32) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 28-31, wherein the subscript m is 1,    and W₁ is C₁₋₄ alkylene.

-   33) A compound or pharmaceutically acceptable salt thereof,    according to clause 32, wherein the subscript m is 1, L₁ is as    defined above and W₁ is —CH₂—, —CH₂—CH₂—, —C(CH₃)H—, —CH₂—CH₂—CH₂—    or —CH₂—C(CH₃)H—.

-   34) A compound or pharmaceutically acceptable salt thereof,    according to clause 28, or 29, wherein the subscript m is 0.

-   35) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 28-34, wherein L₂ is absent.

-   36) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 28-34, wherein L₂ is —O—.

-   37) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 28-34, wherein L₂ is —C(═O)—.

-   38) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 28-34, wherein L₂ is —C(═O)O— or    —OC(═O)—.

-   39) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 28-34, wherein L₂ is    —C(═O)—C(═O)NR^(a)—.

-   40) A compound or pharmaceutically acceptable salt thereof,    according to clause 39, wherein R^(a) is H.

-   41) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 28-34, wherein L₂ is —NR^(b)—.

-   42) A compound or pharmaceutically acceptable salt thereof,    according to clause 41, wherein R^(b) is H.

-   43) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 28-34, wherein L₂ is —C(═O)NR^(c)—.

-   44) A compound or pharmaceutically acceptable salt thereof,    according to clause 41, wherein R^(c) is H, —CH₃, or —CH₂—CH₃.

-   45) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 28-34, wherein L₂ is —NR^(d)C(═O)—.

-   46) A compound or pharmaceutically acceptable salt thereof,    according to clause 45, wherein R^(d) is H, —CH₃, or —CH₂—CH₃.

-   47) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 28-34, wherein L₂ is —SO₂—.

-   48) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 28-34, wherein L₂ is —SO₂NR^(e)—.

-   49) A compound or pharmaceutically acceptable salt thereof,    according to clause 48, wherein R^(e) is H, —CH₃, or —CH₂—CH₃.

-   50) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 28-34, wherein L₂ is —NR^(f)SO₂—.

-   51) A compound or pharmaceutically acceptable salt thereof,    according to clause 50, wherein R^(f) is H, —CH₃, or —CH₂—CH₃.

-   52) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 28-51, wherein G₁ is H, or CN.

-   53) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 28-51, wherein G₁ is C₁₋₄ alkyl.

-   54) A compound or pharmaceutically acceptable salt thereof,    according to clause 53, wherein G₁ is —CH₃, or —CH₂—CH₃.

-   55) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 28-51, wherein G₁ is C₁₋₄ alkyl    substituted with —CN, OH, halo or phenyl.

-   56) A compound or pharmaceutically acceptable salt thereof,    according to clause 55, wherein G₁ is —CF₃, —CH₂—Cl, —CH₂—CN,    —CH₂—OH or —CH₂-Ph.

-   57) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 28-51, wherein G₁ is C₃₋₇    cycloalkyl.

-   58) A compound or pharmaceutically acceptable salt thereof,    according to clause 57, wherein G₁ is cyclopropyl, cyclobutyl,    cyclopropyl, or cyclohexyl.

-   59) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 28-51, wherein G₁ is C₃₋₇ cycloalkyl    substituted with —NH₂.

-   60) A compound or pharmaceutically acceptable salt thereof,    according to clause 59, wherein G₁ is cyclopropyl, cyclobutyl,    cyclopropyl, or cyclohexyl, each of which is substituted with —NH₂.

-   61) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 28-51, wherein G₁ is 5-6 membered    heterocycloalkenyl containing 1 double bond containing one to three    heteroatoms independently selected from O, N, and S.

-   62) A compound or pharmaceutically acceptable salt thereof,    according to clause 61, wherein G₁ is dihydrofuranyl,    dihydrothiazolyl, dihydrooxazolyl, dihydropyranyl, or    dihydrothiopyranyl.

-   63) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 28-51, wherein G₁ is 4-10 membered    mono, bi or spirocyclic heterocycloalkyl containing one to three    heteroatoms independently selected from O, N, and S.

-   64) A compound or pharmaceutically acceptable salt thereof,    according to clause 63, wherein G₁ is oxetanyl, azetidinyl,    tetrahydrofuranyl, pyrolidinyl, tetrahydropyranyl, piperidinyl,    piperazinyl, morpholinyl, thiomorpholinyl, or    2,6-Diaza-spiro[3.3]heptane.

-   65) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 28-51, wherein G₁ is 4-10 membered    mono, bi or spirocyclic heterocycloalkyl containing one to three    heteroatoms independently selected from O, N, and S, substituted    with one or two independently selected R⁹.

-   66) A compound or pharmaceutically acceptable salt thereof,    according to clause 65, wherein G₁ is oxetanyl, azetidinyl,    tetrahydrofuranyl, pyrolidinyl, tetrahydropyranyl, piperidinyl,    piperazinyl, morpholinyl, thiomorpholinyl, or    2,6-Diaza-spiro[3.3]heptane, each of which is substituted with one    or two independently selected R⁹.

-   67) A compound or pharmaceutically acceptable salt thereof,    according to clause 65 or 66, wherein R⁹ is oxo.

-   68) A compound or pharmaceutically acceptable salt thereof,    according to clause 65 or 66, wherein R⁹ is R¹⁰ and R¹⁰ is selected    from OH, F, Cl, and —CN.

-   69) A compound or pharmaceutically acceptable salt thereof,    according to clause 65 or 66, wherein R⁹ is R¹⁰ and R¹⁰ is selected    from —CH₃, —CH₂—CH₃, —CF₃, —CH₂—CH₂—OH, —CH₂-phenyl,

-   70) A compound or pharmaceutically acceptable salt thereof,    according to clause 65 or 66, wherein R⁹ is R¹⁰ and R¹⁰ is selected    from —OCH₃, —OCH₂—CH₃, and —OC(CH₃)₃.

-   71) A compound or pharmaceutically acceptable salt thereof,    according to clause 65 or 66, wherein R⁹ is R¹⁰ and R¹¹ is selected    from —SO₂CH₃, —C(═O)OCH₃, and —C(═O)CH₃.

-   72) A compound or pharmaceutically acceptable salt thereof,    according to clause 65 or 66, wherein each R⁹ is R¹⁰ and R¹⁰ is    —NR^(g)C(═O)CH₃, or —NR^(g)C(═O)CH₂CH₃.

-   73) A compound or pharmaceutically acceptable salt thereof,    according to clause 72, wherein each R^(g) is H, —CH₃, or —CH₂CH₃.

-   74) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 28-51, wherein G₁ is 5-6 membered    heteroaryl containing one to three heteroatoms independently    selected from O, N, and S.

-   75) A compound or pharmaceutically acceptable salt thereof,    according to clause 74, wherein G₁ is furanyl, thienyl, pyrrolyl,    pyrazolyl, imidazolyl, triazolyl, oxazolyl, oxadiazolyl, thiazolyl,    thiadiazolyl, pyridyl, pyrazinyl, or pyrimidyl.

-   76) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 28-51, wherein G₁ is 5-6 membered    heteroaryl containing one to three heteroatoms independently    selected from O, N, and S, substituted with one or two independently    selected R¹⁰.

-   77) A compound or pharmaceutically acceptable salt thereof,    according to clause 76, wherein G₁ is furanyl, thienyl, pyrolyl,    pyrazolyl, imidazolyl, triazolyl, oxazolyl, oxadiazolyl, thiazolyl,    thiadiazolyl, pyridyl, pyrazinyl, or pyrimidyl, each of which is    substituted with one or two independently selected R¹⁰.

-   78) A compound or pharmaceutically acceptable salt thereof,    according to clause 77, wherein R¹⁰ is selected from OH, F, Cl, and    —CN.

-   79) A compound or pharmaceutically acceptable salt thereof,    according to clause 77, wherein R¹⁰ is selected from —CH₃, —CH₂—CH₃,    —CF₃, —CH₂—CH₂—OH, and —CH₂-phenyl.

-   80) A compound or pharmaceutically acceptable salt thereof,    according to clause 77, wherein R¹⁰ is selected from —OCH₃,    —OCH₂—CH₃, and —OC(CH₃)₃.

-   81) A compound or pharmaceutically acceptable salt thereof,    according to clause 77, wherein R¹⁰ is selected from —SO₂CH₃,    —C(═O)OCH₃, and —C(═O)CH₃.

-   82) A compound or pharmaceutically acceptable salt thereof,    according to clause 77, wherein each R¹⁰ is —NR^(g)C(═O)CH₃, or    —NR^(g)C(═O)CH₂CH₃.

-   83) A compound or pharmaceutically acceptable salt thereof,    according to clause 82, wherein each R^(g) is H, —CH₃, or —CH₂CH₃.

-   84) A compound according to clause 1, wherein the compound is    according to Formula Va, Vb, Vc, or Vd:

-   -   wherein R^(6a), R^(6b), W₁, and G₁ are according to clause 1.

-   85) A compound or pharmaceutically acceptable salt thereof,    according to clause 84, wherein W₁ is C₁₋₄ alkylene.

-   86) A compound or pharmaceutically acceptable salt thereof,    according to clause 85, wherein W₁ is —CH₂—, —CH₂—CH₂—, —C(CH₃)H—,    —CH₂—CH₂—CH₂— or —CH₂—C(CH₃)H—.

-   87) A compound according to clause 1, wherein the compound is    according to Formula VIa, VIb, VIc, or VId:

-   -   wherein R^(6a), R^(6b), and G₁ are according to clause 1.

-   88) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 84-87, wherein G₁ is 4-7 membered    heterocycloalkyl containing one or more heteroatoms independently    selected from O, N, and S.

-   89) A compound or pharmaceutically acceptable salt thereof,    according to clause 88, wherein G₁ is oxetanyl, azetidinyl,    tetrahydrofuranyl, pyrolidinyl, tetrahydropyranyl, piperidinyl,    piperazinyl, morpholinyl, or thiomorpholinyl.

-   90) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 84-87, wherein G₁ is 4-7 membered    heterocycloalkyl containing one or more heteroatoms independently    selected from O, N, and S, which heterocycloalkyl is substituted    with one or two independently selected R⁹ groups.

-   91) A compound or pharmaceutically acceptable salt thereof,    according to clause 90, wherein G₁ is oxetanyl, azetidinyl,    tetrahydrofuranyl, pyrolidinyl, tetrahydropyranyl, piperidinyl,    piperazinyl, morpholinyl, or thiomorpholinyl, each of which is    substituted with one or two independently selected R⁹ groups.

-   92) A compound or pharmaceutically acceptable salt thereof,    according to clause 90 or 91, wherein R⁹ is oxo.

-   93) A compound or pharmaceutically acceptable salt thereof,    according to clause 90 or 91, wherein R⁹ is R¹⁰ and R¹⁰ is selected    from OH, F, Cl, and —CN.

-   94) A compound or pharmaceutically acceptable salt thereof,    according to clause 90 or 91, wherein R⁹ is R¹⁰ and R¹⁰ is selected    from —CH₃, —CH₂—CH₃, —CF₃, —CH₂—CH₂—OH, and —CH₂-phenyl.

-   95) A compound or pharmaceutically acceptable salt thereof,    according to clause 90 or 91, wherein R⁹ is R¹⁰ and R¹⁰ is selected    from —OCH₃, —OCH₂—CH₃, and —OC(CH₃)₃.

-   96) A compound or pharmaceutically acceptable salt thereof,    according to clause 90 or 91, wherein R⁹ is R¹⁰ and R¹⁰ is selected    from —SO₂CH₃, —C(═O)OCH₃, and —C(═O)CH₃.

-   97) A compound or pharmaceutically acceptable salt thereof,    according to clause 90 or 91, wherein R⁹ is R¹⁰ and R¹⁰ is    —NR^(g)C(═O)CH₃, or —NR^(g)C(═O)CH₂CH₃.

-   98) A compound or pharmaceutically acceptable salt thereof,    according to clause 90 or 91, wherein each R^(g) is H, —CH₃, or    —CH₂CH₃.

-   99) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-98, wherein R^(6a) is H, —CH₃ or    F, and R^(6b) is H.

-   100) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-98, wherein R^(6a) is CH₃, and    R^(6b) is H.

-   101) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-98, wherein R^(6a) is H, and    R^(6b) is H, —CH₃ or F.

-   102) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-98, wherein R^(6a) and R^(6b) are    H.

-   103) A compound or pharmaceutically acceptable salt thereof, wherein    the compound is selected from the compounds of Table III.

-   104) A compound or pharmaceutically acceptable salt thereof, wherein    the compound is    2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile.

-   105) A pharmaceutical composition comprising a pharmaceutically    acceptable carrier and a pharmaceutically effective amount of a    compound according to any one of clauses 1-104.

-   106) A pharmaceutical composition according to clause 105,    comprising a further therapeutic agent.

-   107) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-104, or a pharmaceutical    composition according to clause 105 or 106, for use in medicine.

-   108) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-104, or a pharmaceutical    composition according to clause 105 or 106, for use in the treatment    of fibrotic diseases, proliferative diseases, inflammatory diseases,    autoimmune diseases, respiratory diseases, cardiovascular diseases,    neurodegenerative diseases, dermatological disorders, and/or    abnormal angiogenesis associated diseases.

-   109) A compound or pharmaceutically acceptable salt thereof,    according to any one of clauses 1-104, or a pharmaceutical    composition according to clause 105 or 106, for use in the treatment    of idiopathic pulmonary fibrosis.

-   110) The use of a compound or pharmaceutically acceptable salt    thereof or the pharmaceutical composition according to clause 108 or    109, wherein said compound or pharmaceutical composition is    administered in combination with a further therapeutic agent.

-   111) A method for the treatment, or prevention of diseases or    conditions selected from fibrotic diseases, proliferative diseases,    inflammatory diseases, autoimmune diseases, respiratory diseases,    cardiovascular diseases, neurodegenerative diseases, dermatological    disorders, and/or abnormal angiogenesis associated diseases,    comprising administering an amount of compound according to any one    of clauses 1-104, or the pharmaceutical composition according any    one of clauses 105 or 106, sufficient to effect said treatment, or    prevention.

-   112) A method for the treatment, or prevention of diseases or    conditions selected from idiopathic pulmonary fibrosis, comprising    administering an amount of compound according to any one of clauses    1-104, or the pharmaceutical composition according any one of    clauses 105 or 106, sufficient to effect said treatment, or    prevention.

-   113) The method according to clause 111 or 112, wherein the    compound, or the pharmaceutical composition, is administered in    combination with a further therapeutic agent.

-   114) The pharmaceutical composition according to clause 106, or the    use according to clause 110, or the method according to clause 113,    wherein the further therapeutic agent is for the treatment of    fibrotic diseases, proliferative diseases, inflammatory diseases,    autoimmune diseases, respiratory diseases, cardiovascular diseases,    neurodegenerative diseases, dermatological disorders, and/or    abnormal angiogenesis associated diseases.

-   115) The pharmaceutical composition according to clause 106, or the    use according to clause 110, or the method according to clause 113,    wherein the further therapeutic agent is for the treatment of    idiopathic pulmonary fibrosis.

Pharmaceutical Compositions

When employed as a pharmaceutical, a compound of the invention istypically administered in the form of a pharmaceutical composition. Suchcompositions can be prepared in a manner well known in thepharmaceutical art and comprise at least one active compound of theinvention according to Formula I. Generally, a compound of the inventionis administered in a pharmaceutically effective amount. The amount ofcompound of the invention actually administered will typically bedetermined by a physician, in the light of the relevant circumstances,including the condition to be treated, the chosen route ofadministration, the actual compound of the invention administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

The pharmaceutical compositions of this invention can be administered bya variety of routes including oral, rectal, transdermal, subcutaneous,intra-articular, intravenous, intramuscular, and intranasal. Dependingon the intended route of delivery, a compound of the invention ispreferably formulated as either injectable or oral compositions or assalves, as lotions or as patches all for transdermal administration.

The compositions for oral administration can take the form of bulkliquid solutions or suspensions, or bulk powders. More commonly,however, the compositions are presented in unit dosage forms tofacilitate accurate dosing. The term ‘unit dosage forms’ refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient, vehicle orcarrier. Typical unit dosage forms include prefilled, premeasuredampules or syringes of the liquid compositions or pills, tablets,capsules or the like in the case of solid compositions. In suchcompositions, the compound of the invention according to Formula I isusually a minor component (from about 0.1 to about 50% by weight orpreferably from about 1 to about 40% by weight) with the remainder beingvarious vehicles or carriers and processing aids helpful for forming thedesired dosing form.

Liquid forms suitable for oral administration may include a suitableaqueous or non-aqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compound of the inventionsof a similar nature: a binder such as microcrystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, or corn starch; alubricant such as magnesium stearate; a glidant such as colloidalsilicon dioxide; a sweetening agent such as sucrose or saccharin; or aflavoring agent such as peppermint or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable carriers knownin the art. As before, the active compound of the invention according toFormula I in such compositions is typically a minor component, oftenbeing from about 0.05 to 10% by weight with the remainder being theinjectable carrier and the like.

Transdermal compositions are typically formulated as a topical ointmentor cream containing the active ingredient(s), generally in an amountranging from about 0.01 to about 20% by weight, preferably from about0.1 to about 20% by weight, preferably from about 0.1 to about 10% byweight, and more preferably from about 0.5 to about 15% by weight. Whenformulated as an ointment, the active ingredients will typically becombined with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredients may be formulated in a cream with,for example an oil-in-water cream base. Such transdermal formulationsare well-known in the art and generally include additional ingredientsto enhance the dermal penetration of stability of the active ingredientsor the formulation. All such known transdermal formulations andingredients are included within the scope of this invention.

A compound of the invention can also be administered by a transdermaldevice. Accordingly, transdermal administration can be accomplishedusing a patch either of the reservoir or porous membrane type, or of asolid matrix variety.

The above-described components for orally administrable, injectable ortopically administrable compositions are merely representative. Othermaterials as well as processing techniques and the like are set forth inPart 8 of Remington's Pharmaceutical Sciences, 17^(th) edition, 1985,Mack Publishing Company, Easton, Pa., which is incorporated herein byreference.

A compound of the invention can also be administered in sustainedrelease forms or from sustained release drug delivery systems. Adescription of representative sustained release materials can be foundin Remington's Pharmaceutical Sciences.

The following formulation examples illustrate representativepharmaceutical compositions that may be prepared in accordance with thisinvention. The present invention, however, is not limited to thefollowing pharmaceutical compositions.

Formulation 1 Tablets

A compound of the invention according to Formula I may be admixed as adry powder with a dry gelatin binder in an approximate 1:2 weight ratio.A minor amount of magnesium stearate may be added as a lubricant. Themixture may be formed into 240-270 mg tablets (80-90 mg of activecompound of the invention according to Formula I per tablet) in a tabletpress.

Formulation 2 Capsules

A compound of the invention according to Formula I may be admixed as adry powder with a starch diluent in an approximate 1:1 weight ratio. Themixture may be filled into 250 mg capsules (125 mg of active compound ofthe invention according to Formula I per capsule).

Formulation 3 Liquid

A compound of the invention according to Formula I (125 mg), may beadmixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultantmixture may be blended, passed through a No. 10 mesh U.S. sieve, andthen mixed with a previously made solution of microcrystalline celluloseand sodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodiumbenzoate (10 mg), flavor, and color may be diluted with water and addedwith stirring. Sufficient water may then be added with stirring. Furthersufficient water may be then added to produce a total volume of 5 mL.

Formulation 4 Tablets

A compound of the invention according to Formula I may be admixed as adry powder with a dry gelatin binder in an approximate 1:2 weight ratio.A minor amount of magnesium stearate may be added as a lubricant. Themixture may be formed into 450-900 mg tablets (150-300 mg of activecompound of the invention according to Formula I) in a tablet press.

Formulation 5 Injection

A compound of the invention according to Formula I may be dissolved orsuspended in a buffered sterile saline injectable aqueous medium to aconcentration of approximately 5 mg/mL.

Formulation 6 Topical

Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted atabout 75° C. and then a mixture of A compound of the invention accordingto Formula I (50 g) methylparaben (0.25 g), propylparaben (0.15 g),sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved inwater (about 370 g) may be added and the resulting mixture may bestirred until it congeals.

Methods of Treatment

In one embodiment, the present invention provides compounds of theinvention, or pharmaceutical compositions comprising a compound of theinvention, for use in medicine. In a particular embodiment, the presentinvention provides compounds of the invention or pharmaceuticalcompositions comprising a compound of the invention, for use in theprophylaxis and/or treatment of fibrotic diseases, proliferativediseases, inflammatory diseases, autoimmune diseases, respiratorydiseases, cardiovascular diseases, neurodegenerative diseases,dermatological disorders, and/or abnormal angiogenesis associateddiseases.

In another embodiment, the present invention provides compounds of theinvention, or pharmaceutical compositions comprising a compound of theinvention for use in the manufacture of a medicament for use in theprophylaxis and/or treatment of fibrotic diseases, proliferativediseases, inflammatory diseases, autoimmune diseases, respiratorydiseases, cardiovascular diseases, neurodegenerative diseases,dermatological disorders, and/or abnormal angiogenesis associateddiseases.

In one embodiment, the present invention provides pharmaceuticalcompositions comprising a compound of the invention, and anothertherapeutic agent. In a particular embodiment, the other therapeuticagent is a fibrotic diseases, proliferative diseases, inflammatorydiseases, autoimmune diseases, respiratory diseases, cardiovasculardiseases, neurodegenerative diseases, dermatological disorders, and/orabnormal angiogenesis associated diseases treatment agent.

In additional method of treatment aspects, this invention providesmethods of prophylaxis and/or treatment of a mammal afflicted withfibrotic diseases, proliferative diseases, inflammatory diseases,autoimmune diseases, respiratory diseases, cardiovascular diseases,neurodegenerative diseases, dermatological disorders, and/or abnormalangiogenesis associated diseases, which methods comprise theadministration of an effective amount of a compound of the invention orone or more of the pharmaceutical compositions herein described for thetreatment or prophylaxis of said condition.

In one embodiment, the present invention provides compounds of theinvention or pharmaceutical compositions comprising a compound of theinvention, for use in the prophylaxis and/or treatment of fibroticdiseases. In a particular embodiment, the fibrotic disease is selectedfrom idiopathic pulmonary fibrosis (IPF), cystic fibrosis, other diffuseparenchymal lung diseases of different etiologies including iatrogenicdrug-induced fibrosis, occupational and/or environmental inducedfibrosis, granulomatous diseases (sarcoidosis, hypersensitivitypneumonia), collagen vascular disease, alveolar proteinosis, langerhanscell granulomatosis, lymphangioleiomyomatosis, inherited diseases(Hermansky-Pudlak Syndrome, tuberous sclerosis, neurofibromatosis,metabolic storage disorders, familial interstitial lung disease),radiation induced fibrosis, chronic obstructive pulmonary disease(COPD), scleroderma, bleomycin induced pulmonary fibrosis, chronicasthma, silicosis, asbestos induced pulmonary fibrosis, acuterespiratory distress syndrome (ARDS), kidney fibrosis,tubulointerstitium fibrosis, glomerular nephritis, focal segmentalglomerular sclerosis, IgA nephropathy, hypertension, Alport, gutfibrosis, liver fibrosis, cirrhosis, alcohol induced liver fibrosis,toxic/drug induced liver fibrosis, hemochromatosis, nonalcoholicsteatohepatitis (NASH), biliary duct injury, primary biliary cirrhosis,infection induced liver fibrosis, viral induced liver fibrosis, andautoimmune hepatitis, corneal scarring, hypertrophic scarring, Dupuytrendisease, keloids, cutaneous fibrosis, cutaneous scleroderma, systemicsclerosis, spinal cord injury/fibrosis, myelofibrosis, vascularrestenosis, atherosclerosis, arteriosclerosis, Wegener's granulomatosis,Peyronie's disease, or chronic lymphocytic. More particularly, thefibrotic diseases is idiopathic pulmonary fibrosis (IPF).

In another embodiment, the present invention provides compounds of theinvention, or pharmaceutical compositions comprising a compound of theinvention for use in the manufacture of a medicament for use in theprophylaxis and/or treatment of fibrotic diseases. In a particularembodiment, the fibrotic disease is selected from idiopathic pulmonaryfibrosis (IPF), cystic fibrosis, other diffuse parenchymal lung diseasesof different etiologies including iatrogenic drug-induced fibrosis,occupational and/or environmental induced fibrosis, granulomatousdiseases (sarcoidosis, hypersensitivity pneumonia), collagen vasculardisease, alveolar proteinosis, langerhans cell granulomatosis,lymphangioleiomyomatosis, inherited diseases (Hermansky-Pudlak Syndrome,tuberous sclerosis, neurofibromatosis, metabolic storage disorders,familial interstitial lung disease), radiation induced fibrosis, chronicobstructive pulmonary disease (COPD), scleroderma, bleomycin inducedpulmonary fibrosis, chronic asthma, silicosis, asbestos inducedpulmonary fibrosis, acute respiratory distress syndrome (ARDS), kidneyfibrosis, tubulointerstitium fibrosis, glomerular nephritis, focalsegmental glomerular sclerosis, IgA nephropathy, hypertension, Alport,gut fibrosis, liver fibrosis, cirrhosis, alcohol induced liver fibrosis,toxic/drug induced liver fibrosis, hemochromatosis, nonalcoholicsteatohepatitis (NASH), biliary duct injury, primary biliary cirrhosis,infection induced liver fibrosis, viral induced liver fibrosis, andautoimmune hepatitis, corneal scarring, hypertrophic scarring, Dupuytrendisease, keloids, cutaneous fibrosis, cutaneous scleroderma, systemicsclerosis, spinal cord injury/fibrosis, myelofibrosis, vascularrestenosis, atherosclerosis, arteriosclerosis, Wegener's granulomatosis,Peyronie's disease, or chronic lymphocytic. More particularly, thefibrotic disease is idiopathic pulmonary fibrosis (IPF).

In additional method of treatment aspects, this invention providesmethods of prophylaxis and/or treatment of a mammal afflicted withfibrotic diseases, which methods comprise the administration of aneffective amount of a compound of the invention or one or more of thepharmaceutical compositions herein described for the treatment orprophylaxis of said condition. In a particular embodiment, the fibroticdisease is selected from idiopathic pulmonary fibrosis (IPF), cysticfibrosis, other diffuse parenchymal lung diseases of differentetiologies including iatrogenic drug-induced fibrosis, occupationaland/or environmental induced fibrosis, granulomatous diseases(sarcoidosis, hypersensitivity pneumonia), collagen vascular disease,alveolar proteinosis, langerhans cell granulomatosis,lymphangioleiomyomatosis, inherited diseases (Hermansky-Pudlak Syndrome,tuberous sclerosis, neurofibromatosis, metabolic storage disorders,familial interstitial lung disease), radiation induced fibrosis, chronicobstructive pulmonary disease (COPD), scleroderma, bleomycin inducedpulmonary fibrosis, chronic asthma, silicosis, asbestos inducedpulmonary fibrosis, acute respiratory distress syndrome (ARDS), kidneyfibrosis, tubulointerstitium fibrosis, glomerular nephritis, focalsegmental glomerular sclerosis, IgA nephropathy, hypertension, Alport,gut fibrosis, liver fibrosis, cirrhosis, alcohol induced liver fibrosis,toxic/drug induced liver fibrosis, hemochromatosis, nonalcoholicsteatohepatitis (NASH), biliary duct injury, primary biliary cirrhosis,infection induced liver fibrosis, viral induced liver fibrosis, andautoimmune hepatitis, corneal scarring, hypertrophic scarring, Dupuytrendisease, keloids, cutaneous fibrosis, cutaneous scleroderma, systemicsclerosis, spinal cord injury/fibrosis, myelofibrosis, vascularrestenosis, atherosclerosis, arteriosclerosis, Wegener's granulomatosis,Peyronie's disease, or chronic lymphocytic. More particularly, thefibrotic disease is idiopathic pulmonary fibrosis (IPF).

A particular regimen of the present method comprises the administrationto a subject suffering from a fibrotic disease of an effective amount ofa compound of the invention according to Formula I for a period of timesufficient to reduce the level of fibrosis in the subject, andpreferably terminate the processes responsible for said fibrosis. Aspecial embodiment of the method comprises administering of an effectiveamount of a compound of the invention according to Formula I to asubject patient suffering from to the development of idiopathicpulmonary fibrosis, for a period of time sufficient to reduce or preventidiopathic pulmonary fibrosis of said patient, and preferably terminate,the processes responsible for said idiopathic pulmonary fibrosis.

In one embodiment, the present invention provides compounds of theinvention or pharmaceutical compositions comprising a compound of theinvention, for use in the prophylaxis and/or treatment of proliferativediseases. In a particular embodiment, the proliferative disease isselected from cancer, leukemia, multiple myeloma and psoriasis.

In another embodiment, the present invention provides compounds of theinvention, or pharmaceutical compositions comprising a compound of theinvention for use in the manufacture of a medicament for use in theprophylaxis and/or treatment of proliferative diseases. In a particularembodiment, the proliferative disease is selected from cancer, leukemia,multiple myeloma and psoriasis.

In additional method of treatment aspects, this invention providesmethods of prophylaxis and/or treatment of a mammal afflicted withproliferative diseases, which methods comprise the administration of aneffective amount of a compound of the invention or one or more of thepharmaceutical compositions herein described for the treatment orprophylaxis of said condition. In a particular embodiment, theproliferative disease is selected from cancer, leukemia, multiplemyeloma and psoriasis.

In one embodiment, the present invention provides compounds of theinvention or pharmaceutical compositions comprising a compound of theinvention, for use in the prophylaxis and/or treatment of inflammatorydiseases. In a particular embodiment, the inflammatory disease isselected from rheumatoid arthritis, osteoarthritis, allergic airwaydisease (e.g. asthma), chronic obstructive pulmonary disease (COPD) andinflammatory bowel diseases (e.g. Crohn's disease and ulcerativecolitis). More particularly, the inflammatory disease is selected fromrheumatoid arthritis, and chronic obstructive pulmonary disease (COPD).

In another embodiment, the present invention provides compounds of theinvention, or pharmaceutical compositions comprising a compound of theinvention for use in the manufacture of a medicament for use in theprophylaxis and/or treatment of inflammatory diseases. In a particularembodiment, the inflammatory disease is selected from rheumatoidarthritis, osteoarthritis, allergic airway disease (e.g. asthma),chronic obstructive pulmonary disease (COPD) and inflammatory boweldiseases (e.g. Crohn's disease and ulcerative colitis). Moreparticularly, the inflammatory disease is selected from rheumatoidarthritis, and chronic obstructive pulmonary disease (COPD).

In additional method of treatment aspects, this invention providesmethods of prophylaxis and/or treatment of a mammal afflicted withinflammatory diseases, which methods comprise the administration of aneffective amount of a compound of the invention or one or more of thepharmaceutical compositions herein described for the treatment orprophylaxis of said condition. In a particular embodiment, theinflammatory disease is selected from rheumatoid arthritis,osteoarthritis, allergic airway disease (e.g. asthma), chronicobstructive pulmonary disease (COPD) and inflammatory bowel diseases(e.g. Crohn's disease and ulcerative colitis). More particularly theinflammatory disease is selected from rheumatoid arthritis, and chronicobstructive pulmonary disease (COPD).

In one embodiment, the present invention provides compounds of theinvention or pharmaceutical compositions comprising a compound of theinvention, for use in the prophylaxis and/or treatment of autoimmunediseases. In a particular embodiment, the autoimmune disease is selectedfrom COPD, asthma (e.g intrinsic asthma, extrinsic asthma, dust asthma,infantily asthma) particularly chronic or inveterate asthma (for examplelate asthma and airway hyperreponsiveness), bronchitis, includingbronchial asthma, systemic lupus erythematosus (SLE), cutaneous lupuserythrematosis, lupus nephritis, dermatomyositis, Sjogren's syndrome,multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitusand complications associated therewith, atopic eczema (atopicdermatitis), thyroiditis (Hashimoto's and autoimmune thyroiditis),contact dermatitis and further eczematous dermatitis, inflammatory boweldisease (e.g. Crohn's disease and ulcerative colitis), atherosclerosisand amyotrophic lateral sclerosis. Particularly, the autoimmune diseaseis selected from COPD, asthma, systemic lupus erythematosis, type Idiabetes mellitus and inflammatory bowel disease.

In another embodiment, the present invention provides compounds of theinvention, or pharmaceutical compositions comprising a compound of theinvention for use in the manufacture of a medicament for use in theprophylaxis and/or treatment of autoimmune diseases. In a particularembodiment, the autoimmune disease is selected from COPD, asthma (e.gintrinsic asthma, extrinsic asthma, dust asthma, infantily asthma)particularly chronic or inveterate asthma (for example late asthma andairway hyperreponsiveness), bronchitis, including bronchial asthma,systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis,lupus nephritis, dermatomyositis, Sjogren's syndrome, multiplesclerosis, psoriasis, dry eye disease, type I diabetes mellitus andcomplications associated therewith, atopic eczema (atopic dermatitis),thyroiditis (Hashimoto's and autoimmune thyroiditis), contact dermatitisand further eczematous dermatitis, inflammatory bowel disease (e.g.Crohn's disease and ulcerative colitis), atherosclerosis and amyotrophiclateral sclerosis. Particularly, the autoimmune disease is selected fromCOPD, asthma, systemic lupus erythematosis, type I diabetes mellitus andinflammatory bowel disease.

In additional method of treatment aspects, this invention providesmethods of prophylaxis and/or treatment of a mammal afflicted withautoimmune diseases, which methods comprise the administration of aneffective amount of a compound of the invention or one or more of thepharmaceutical compositions herein described for the treatment orprophylaxis of said condition. In a particular embodiment, theautoimmune disease is selected from COPD, asthma (e.g intrinsic asthma,extrinsic asthma, dust asthma, infantily asthma) particularly chronic orinveterate asthma (for example late asthma and airwayhyperreponsiveness), bronchitis, including bronchial asthma, systemiclupus erythematosus (SLE), cutaneous lupus erythrematosis, lupusnephritis, dermatomyositis, Sjogren's syndrome, multiple sclerosis,psoriasis, dry eye disease, type I diabetes mellitus and complicationsassociated therewith, atopic eczema (atopic dermatitis), thyroiditis(Hashimoto's and autoimmune thyroiditis), contact dermatitis and furthereczematous dermatitis, inflammatory bowel disease (e.g. Crohn's diseaseand ulcerative colitis), atherosclerosis and amyotrophic lateralsclerosis. Particularly, the autoimmune disease is selected from COPD,asthma, systemic lupus erythematosis, type I diabetes mellitus andinflammatory bowel disease.

In one embodiment, the present invention provides compounds of theinvention or pharmaceutical compositions comprising a compound of theinvention, for use in the prophylaxis and/or treatment of respiratorydiseases. In a particular embodiment, the respiratory disease isselected from asthma, adult respiratory distress syndrome and allergic(extrinsic) asthma, non-allergic (intrinsic) asthma, acute severeasthma, chronic asthma, clinical asthma, nocturnal asthma,allergen-induced asthma, aspirin-sensitive asthma, exercise-inducedasthma, isocapnic hyperventilation, child onset asthma, adult-onsetasthma, cough-variant asthma, occupational asthma, steroid-resistantasthma, seasonal asthma, seasonal allergic rhinitis, perennial allergicrhinitis, chronic obstructive pulmonary disease, including chronicbronchitis or emphysema, pulmonary hypertension, interstitial lungfibrosis and/or airway inflammation and cystic fibrosis, and hypoxia.

In another embodiment, the present invention provides compounds of theinvention, or pharmaceutical compositions comprising a compound of theinvention for use in the manufacture of a medicament for use in theprophylaxis and/or treatment of respiratory diseases. In a particularembodiment, the respiratory disease is selected from asthma, adultrespiratory distress syndrome and allergic (extrinsic) asthma,non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma,clinical asthma, nocturnal asthma, allergen-induced asthma,aspirin-sensitive asthma, exercise-induced asthma, isocapnichyperventilation, child onset asthma, adult-onset asthma, cough-variantasthma, occupational asthma, steroid-resistant asthma, seasonal asthma,seasonal allergic rhinitis, perennial allergic rhinitis, chronicobstructive pulmonary disease, including chronic bronchitis oremphysema, pulmonary hypertension, interstitial lung fibrosis and/orairway inflammation and cystic fibrosis, and hypoxia.

In additional method of treatment aspects, this invention providesmethods of prophylaxis and/or treatment of a mammal afflicted withrespiratory diseases, which methods comprise the administration of aneffective amount of a compound of the invention or one or more of thepharmaceutical compositions herein described for the treatment orprophylaxis of said condition. In a particular embodiment, therespiratory disease is selected from asthma, adult respiratory distresssyndrome and allergic (extrinsic) asthma, non-allergic (intrinsic)asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnalasthma, allergen-induced asthma, aspirin-sensitive asthma,exercise-induced asthma, isocapnic hyperventilation, child onset asthma,adult-onset asthma, cough-variant asthma, occupational asthma,steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis,perennial allergic rhinitis, chronic obstructive pulmonary disease,including chronic bronchitis or emphysema, pulmonary hypertension,interstitial lung fibrosis and/or airway inflammation and cysticfibrosis, and hypoxia.

In one embodiment, the present invention provides compounds of theinvention or pharmaceutical compositions comprising a compound of theinvention, for use in the prophylaxis and/or treatment of cardiovasculardiseases. In a particular embodiment, the cardiovascular disease isselected from arrhythmia (atrial or ventricular or both),atherosclerosis and its sequelae, angina, cardiac rhythm disturbances,myocardial ischemia, myocardial infarction, cardiac or vascularaneurysm, vasculitis, stroke, peripheral obstructive arteriopathy of alimb, an organ, or a tissue, reperfusion injury following ischemia ofthe brain, heart, kidney or other organ or tissue, endotoxic, surgical,or traumatic shock, hypertension, valvular heart disease, heart failure,abnormal blood pressure, shock, vasoconstriction (including thatassociated with migraines), vascular abnormality, inflammation,insufficiency limited to a single organ or tissue.

In another embodiment, the present invention provides compounds of theinvention, or pharmaceutical compositions comprising a compound of theinvention for use in the manufacture of a medicament for use in theprophylaxis and/or treatment of cardiovascular diseases. In a particularembodiment, the cardiovascular disease is selected from arrhythmia(atrial or ventricular or both), atherosclerosis and its sequelae,angina, cardiac rhythm disturbances, myocardial ischemia, myocardialinfarction, cardiac or vascular aneurysm, vasculitis, stroke, peripheralobstructive arteriopathy of a limb, an organ, or a tissue, reperfusioninjury following ischemia of the brain, heart, kidney or other organ ortissue, endotoxic, surgical, or traumatic shock, hypertension, valvularheart disease, heart failure, abnormal blood pressure, shock,vasoconstriction (including that associated with migraines), vascularabnormality, inflammation, insufficiency limited to a single organ ortissue.

In additional method of treatment aspects, this invention providesmethods of prophylaxis and/or treatment of a mammal afflicted withcardiovascular diseases, which methods comprise the administration of aneffective amount of a compound of the invention or one or more of thepharmaceutical compositions herein described for the treatment orprophylaxis of said condition. In a particular embodiment, thecardiovascular disease is selected from arrhythmia (atrial orventricular or both), atherosclerosis and its sequelae, angina, cardiacrhythm disturbances, myocardial ischemia, myocardial infarction, cardiacor vascular aneurysm, vasculitis, stroke, peripheral obstructivearteriopathy of a limb, an organ, or a tissue, reperfusion injuryfollowing ischemia of the brain, heart, kidney or other organ or tissue,endotoxic, surgical, or traumatic shock, hypertension, valvular heartdisease, heart failure, abnormal blood pressure, shock, vasoconstriction(including that associated with migraines), vascular abnormality,inflammation, insufficiency limited to a single organ or tissue.

In one embodiment, the present invention provides compounds of theinvention or pharmaceutical compositions comprising a compound of theinvention, for use in the prophylaxis and/or treatment ofneurodegenerative diseases. In a particular embodiment, theneurodegenerative disease is selected from Alzheimer's disease and otherdementias, brain cancer, degenerative nerve diseases, encephalitis,epilepsy, genetic brain disorders, head and brain malformations,hydrocephalus, stroke, Parkinson's disease, multiple sclerosis,amyotrophic lateral sclerosis (ALS or Lou Gehrig's Disease),Huntington's disease, and prion diseases.

In another embodiment, the present invention provides compounds of theinvention, or pharmaceutical compositions comprising a compound of theinvention for use in the manufacture of a medicament for use in theprophylaxis and/or treatment of neurodegenerative diseases. In aparticular embodiment, the neurodegenerative disease is selected fromAlzheimer's disease and other dementias, brain cancer, degenerativenerve diseases, encephalitis, epilepsy, genetic brain disorders, headand brain malformations, hydrocephalus, stroke, Parkinson's disease,multiple sclerosis, amyotrophic lateral sclerosis (ALS or Lou Gehrig'sDisease), Huntington's disease, and prion diseases.

In additional method of treatment aspects, this invention providesmethods of prophylaxis and/or treatment of a mammal afflicted withneurodegenerative diseases, which methods comprise the administration ofan effective amount of a compound of the invention or one or more of thepharmaceutical compositions herein described for the treatment orprophylaxis of said condition. In a particular embodiment, theneurodegenerative disease is selected from Alzheimer's disease and otherdementias, brain cancer, degenerative nerve diseases, encephalitis,epilepsy, genetic brain disorders, head and brain malformations,hydrocephalus, stroke, Parkinson's disease, multiple sclerosis,amyotrophic lateral sclerosis (ALS or Lou Gehrig's Disease),Huntington's disease, and prion diseases.

In one embodiment, the present invention provides compounds of theinvention or pharmaceutical compositions comprising a compound of theinvention, for use in the prophylaxis and/or treatment of dermatologicaldisorders. In a particular embodiment, the dermatological disease isselected from atopic dermatitis, bullous disorders, collagenoses,psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema,pruritus, urticaria, rosacea, scleroderma, wound healing, scarring,hypertrophic scarring, keloids, Kawasaki Disease, rosacea, orSjogren-Larsso Syndrome.

In another embodiment, the present invention provides compounds of theinvention, or pharmaceutical compositions comprising a compound of theinvention for use in the manufacture of a medicament for use in theprophylaxis and/or treatment of dermatological disorders. In aparticular embodiment, the dermatological disease is selected fromatopic dermatitis, bullous disorders, collagenoses, psoriasis, psoriaticlesions, dermatitis, contact dermatitis, eczema, pruritus, urticaria,rosacea, scleroderma, wound healing, scarring, hypertrophic scarring,keloids, Kawasaki Disease, rosacea, or Sjogren-Larsso Syndrome.

In additional method of treatment aspects, this invention providesmethods of prophylaxis and/or treatment of a mammal afflicted withdermatological disorders, which methods comprise the administration ofan effective amount of a compound of the invention or one or more of thepharmaceutical compositions herein described for the treatment orprophylaxis of said condition. In a particular embodiment, thedermatological disease is selected from atopic dermatitis, bullousdisorders, collagenoses, psoriasis, psoriatic lesions, dermatitis,contact dermatitis, eczema, pruritus, urticaria, rosacea, scleroderma,wound healing, scarring, hypertrophic scarring, keloids, KawasakiDisease, rosacea, or Sjogren-Larsso Syndrome.

In one embodiment, the present invention provides compounds of theinvention or pharmaceutical compositions comprising a compound of theinvention, for use in the prophylaxis and/or treatment of abnormalangiogenesis associated diseases. In a particular embodiment, theabnormal angiogenesis associated disease is selected fromatherosclerosis, hypertension, tumor growth, inflammation, rheumatoidarthritis, wet-form macular degeneration, choroidal neovascularization,retinal neovascularization, diabetic retinopathy, and glioblastomamultiforma.

In another embodiment, the present invention provides compounds of theinvention, or pharmaceutical compositions comprising a compound of theinvention for use in the manufacture of a medicament for use in theprophylaxis and/or treatment of abnormal angiogenesis associateddiseases. In a particular embodiment, the abnormal angiogenesisassociated disease is selected from atherosclerosis, hypertension, tumorgrowth, inflammation, rheumatoid arthritis, wet-form maculardegeneration, choroidal neovascularization, retinal neovascularization,diabetic retinopathy, and glioblastoma multiforma.

In additional method of treatment aspects, this invention providesmethods of prophylaxis and/or treatment of a mammal afflicted withabnormal angiogenesis associated diseases, which methods comprise theadministration of an effective amount of a compound of the invention orone or more of the pharmaceutical compositions herein described for thetreatment or prophylaxis of said condition. In a particular embodiment,the abnormal angiogenesis associated disease is selected fromatherosclerosis, hypertension, tumor growth, inflammation, rheumatoidarthritis, wet-form macular degeneration, choroidal neovascularization,retinal neovascularization, diabetic retinopathy, and glioblastomamultiforma.

Injection dose levels range from about 0.1 mg/kg/h to at least 10mg/kg/h, all for from about 1 to about 120 h and especially 24 to 96 h.A preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more mayalso be administered to achieve adequate steady state levels. Themaximum total dose is not expected to exceed about 1 g/day for a 40 to80 kg human patient.

For the prophylaxis and/or treatment of long-term conditions, such asdegenerative conditions, the regimen for treatment usually stretchesover many months or years so oral dosing is preferred for patientconvenience and tolerance. With oral dosing, one to four (1-4) regulardoses daily, especially one to three (1-3) regular doses daily,typically one to two (1-2) regular doses daily, and most typically one(1) regular dose daily are representative regimens. Alternatively forlong lasting effect drugs, with oral dosing, once every other week, onceweekly, and once a day are representative regimens. In particular,dosage regimen can be every 1-14 days, more particularly 1-10 days, evenmore particularly 1-7 days, and most particularly 1-3 days.

Using these dosing patterns, each dose provides from about 1 to about1000 mg of a compound of the invention, with particular doses eachproviding from about 10 to about 500 mg and especially about 30 to about250 mg.

Transdermal doses are generally selected to provide similar or lowerblood levels than are achieved using injection doses.

When used to prevent the onset of a condition, a compound of theinvention will be administered to a patient at risk for developing thecondition, typically on the advice and under the supervision of aphysician, at the dosage levels described above. Patients at risk fordeveloping a particular condition generally include those that have afamily history of the condition, or those who have been identified bygenetic testing or screening to be particularly susceptible todeveloping the condition.

A compound of the invention can be administered as the sole active agentor it can be administered in combination with other therapeutic agents,including other compound of the inventions that demonstrate the same ora similar therapeutic activity and that are determined to be safe andefficacious for such combined administration. In a specific embodiment,co-administration of two (or more) agents allows for significantly lowerdoses of each to be used, thereby reducing the side effects seen.

In one embodiment, a compound of the invention or a pharmaceuticalcomposition comprising a compound of the invention is administered as amedicament. In a specific embodiment, said pharmaceutical compositionadditionally comprises a further active ingredient.

In one embodiment, a compound of the invention is co-administered withanother therapeutic agent for the treatment and/or prophylaxis of adisease involving inflammation, particular agents include, but are notlimited to, immunoregulatory agents e.g. azathioprine, corticosteroids(e.g. prednisolone or dexamethasone), cyclophosphamide, cyclosporin A,tacrolimus, mycophenolate, mofetil, muromonab-CD3 (OKT3, e.g.Orthocolone®), ATG, aspirin, acetaminophen, ibuprofen, naproxen, andpiroxicam.

In one embodiment, a compound of the invention is co-administered withanother therapeutic agent for the treatment and/or prophylaxis ofarthritis (e.g. rheumatoid arthritis), particular agents include but arenot limited to analgesics, non-steroidal anti-inflammatory drugs(NSAIDS), steroids, synthetic DMARDS (for example but without limitationmethotrexate, leflunomide, sulfasalazine, auranofin, sodiumaurothiomalate, penicillamine, chloroquine, hydroxychloroquine,azathioprine, tofacitinib, baricitinib, fostamatinib, and cyclosporin),and biological DMARDS (for example but without limitation infliximab,etanercept, adalimumab, rituximab, and abatacept).

In one embodiment, a compound of the invention is co-administered withanother therapeutic agent for the treatment and/or prophylaxis ofproliferative disorders, particular agents include but are not limitedto: methotrexate, leukovorin, adriamycin, prednisone, bleomycin,cyclophosphamide, 5-fluorouracil, paclitaxel, docetaxel, vincristine,vinblastine, vinorelbine, doxorubicin, tamoxifen, toremifene, megestrolacetate, anastrozole, goserelin, anti-HER2 monoclonal antibody (e.g.Herceptin™), capecitabine, raloxifene hydrochloride, EGFR inhibitors(e.g. Lressa®, Tarceva™, Erbitux™), VEGF inhibitors (e.g. Avastin™),proteasome inhibitors (e.g. Velcade™), Glivec® and hsp90 inhibitors(e.g. 17-AAG). Additionally, the compound of the invention according toFormula I may be administered in combination with other therapiesincluding, but not limited to, radiotherapy or surgery. In a specificembodiment the proliferative disorder is selected from cancer,myeloproliferative disease or leukaemia.

In one embodiment, a compound of the invention is co-administered withanother therapeutic agent for the treatment and/or prophylaxis ofautoimmune diseases, particular agents include but are not limited to:glucocorticoids, cytostatic agents (e.g. purine analogs), alkylatingagents (e.g nitrogen mustards (cyclophosphamide), nitrosoureas, platinumcompound of the inventions, and others), antimetabolites (e.g.methotrexate, azathioprine and mercaptopurine), cytotoxic antibiotics(e.g. dactinomycin anthracyclines, mitomycin C, bleomycin, andmithramycin), antibodies (e.g. anti-CD20, anti-CD25 or anti-CD3 (OTK3)monoclonal antibodies, Atgam® and Thymoglobuline®), cyclosporin,tacrolimus, rapamycin (sirolimus), interferons (e.g. IFN-β), TNF bindingproteins (e.g. infliximab, etanercept, or adalimumab), mycophenolate,fingolimod and myriocin.

In one embodiment, a compound of the invention is co-administered withanother therapeutic agent for the treatment and/or prophylaxis oftransplant rejection, particular agents include but are not limited to:calcineurin inhibitors (e.g. cyclosporin or tacrolimus (FK506)), mTORinhibitors (e.g. sirolimus, everolimus), anti-proliferatives (e.g.azathioprine, mycophenolic acid), corticosteroids (e.g. prednisolone,hydrocortisone), antibodies (e.g. monoclonal anti-IL-2R^(a) receptorantibodies, basiliximab, daclizumab), polyclonal anti-T-cell antibodies(e.g. anti-thymocyte globulin (ATG), anti-lymphocyte globulin (ALG)).

In one embodiment, a compound of the invention is co-administered withanother therapeutic agent for the treatment and/or prophylaxis of asthmaand/or rhinitis and/or COPD, particular agents include but are notlimited to: beta2-adrenoceptor agonists (e.g. salbutamol, levalbuterol,terbutaline and bitolterol), epinephrine (inhaled or tablets),anticholinergics (e.g. ipratropium bromide), glucocorticoids (oral orinhaled). Long-acting β2-agonists (e.g. salmeterol, formoterol,bambuterol, and sustained-release oral albuterol), combinations ofinhaled steroids and long-acting bronchodilators (e.g.fluticasone/salmeterol, budesonide/formoterol), leukotriene antagonistsand synthesis inhibitors (e.g. montelukast, zafirlukast and zileuton),inhibitors of mediator release (e.g. cromoglycate and ketotifen),biological regulators of IgE response (e.g. omalizumab), antihistamines(e.g. ceterizine, cinnarizine, fexofenadine) and vasoconstrictors (e.g.oxymethazoline, xylomethazoline, nafazoline and tramazoline).

Additionally, a compound of the invention may be administered incombination with emergency therapies for asthma and/or COPD, suchtherapies include oxygen or heliox administration, nebulized salbutamolor terbutaline (optionally combined with an anticholinergic (e.g.ipratropium), systemic steroids (oral or intravenous, e.g. prednisone,prednisolone, methylprednisolone, dexamethasone, or hydrocortisone),intravenous salbutamol, non-specific beta-agonists, injected or inhaled(e.g. epinephrine, isoetharine, isoproterenol, metaproterenol),anticholinergics (IV or nebulized, e.g. glycopyrrolate, atropine,ipratropium), methylxanthines (theophylline, aminophylline,bamiphylline), inhalation anesthetics that have a bronchodilatory effect(e.g. isoflurane, halothane, enflurane), ketamine and intravenousmagnesium sulfate.

In one embodiment, a compound of the invention is co-administered withanother therapeutic agent for the treatment and/or prophylaxis ofinflammatory bowel disease (IBD), particular agents include but are notlimited to: glucocorticoids (e.g. prednisone, budesonide) syntheticdisease modifying, immunomodulatory agents (e.g. methotrexate,leflunomide, sulfasalazine, mesalazine, azathioprine, 6-mercaptopurineand cyclosporin) and biological disease modifying, immunomodulatoryagents (infliximab, adalimumab, rituximab, and abatacept).

In one embodiment, a compound of the invention is co-administered withanother therapeutic agent for the treatment and/or prophylaxis of SLE,particular agents include but are not limited to: human monoclonalantibodies (belimumab (Benlysta)), Disease-modifying antirheumatic drugs(DMARDs) such as antimalarials (e.g. plaquenil, hydroxychloroquine),immunosuppressants (e.g. methotrexate and azathioprine),cyclophosphamide and mycophenolic acid, immunosuppressive drugs andanalgesics, such as nonsteroidal anti-inflammatory drugs, opiates (e.g.dextropropoxyphene and co-codamol), opioids (e.g. hydrocodone,oxycodone, MS Contin, or methadone) and the fentanyl duragesictransdermal patch.

In one embodiment, a compound of the invention is co-administered withanother therapeutic agent for the treatment and/or prophylaxis ofpsoriasis, particular agents include but are not limited to: topicaltreatments such as bath solutions, moisturizers, medicated creams andointments containing coal tar, dithranol (anthralin), corticosteroidslike desoximetasone (Topicort™), fluocinonide, vitamin D3 analogues (forexample, calcipotriol), argan oil and retinoids (etretinate, acitretin,tazarotene), systemic treatments such as methotrexate, cyclosporine,retinoids, tioguanine, hydroxyurea, sulfasalazine, mycophenolatemofetil, azathioprine, tacrolimus, fumaric acid esters or biologics suchas Amevive™, Enbrel™, Humira™, Remicade™, Raptiva™ and ustekinumab (aIL-12 and IL-23 blocker). Additionally, a compound of the invention maybe administered in combination with other therapies including, but notlimited to phototherapy, or photochemotherapy (e.g. psoralen andultraviolet A phototherapy (PUVA)).

In one embodiment, a compound of the invention is co-administered withanother therapeutic agent for the treatment and/or prophylaxis ofallergic reaction, particular agents include but are not limited to:antihistamines (e.g. cetirizine, diphenhydramine, fexofenadine,levocetirizine), glucocorticoids (e.g. prednisone, betamethasone,beclomethasone, dexamethasone), epinephrine, theophylline oranti-leukotrienes (e.g. montelukast or zafirlukast), anti-cholinergicsand decongestants.

By co-administration is included any means of delivering two or moretherapeutic agents to the patient as part of the same treatment regime,as will be apparent to the skilled person. Whilst the two or more agentsmay be administered simultaneously in a single formulation, i.e. as asingle pharmaceutical composition, this is not essential. The agents maybe administered in different formulations and at different times.

Chemical Synthetic Procedures General

The compound of the invention can be prepared from readily availablestarting materials using the following general methods and procedures.It will be appreciated that where typical or preferred processconditions (i.e. reaction temperatures, times, mole ratios of reactants,solvents, pressures, etc.) are given, other process conditions can alsobe used unless otherwise stated. Optimum reaction conditions may varywith the particular reactants or solvent used, but such conditions canbe determined by one skilled in the art by routine optimizationprocedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group as well assuitable conditions for protection and deprotection are well known inthe art (Greene, T W; Wuts, P G M; 1991).

The following methods are presented with details as to the preparationof a compound of the invention as defined hereinabove and thecomparative examples. A compound of the invention may be prepared fromknown or commercially available starting materials and reagents by oneskilled in the art of organic synthesis.

All reagents were of commercial grade and were used as received withoutfurther purification, unless otherwise stated. Commercially availableanhydrous solvents were used for reactions conducted under inertatmosphere. Reagent grade solvents were used in all other cases, unlessotherwise specified. Column chromatography was performed on silica gel60 (35-70 μm). Thin layer chromatography was carried out usingpre-coated silica gel F-254 plates (thickness 0.25 mm). ¹H NMR spectrawere recorded on a Bruker DPX 400 NMR spectrometer (400 MHz or a BrukerAdvance 300 NMR spectrometer (300 MHz). Chemical shifts (δ) for 1H NMRspectra are reported in parts per million (ppm) relative totetramethylsilane (δ 0.00) or the appropriate residual solvent peak,i.e. CHCl₃ (δ 7.27), as internal reference. Multiplicities are given assinglet (s), doublet (d), triplet (t), quartet (q), quintuplet (quin),multiplet (m) and broad (br). Electrospray MS spectra were obtained on aWaters platform LC/MS spectrometer or with Waters Acquity UPLC withWaters Acquity PDA detector and SQD mass spectrometer. Columns used:UPLC BEH C18 1.7 μm 2.1×5 mm VanGuard Pre-column with Acquity UPLC BEHC18 1.7 μm 2.1×30 mm Column or Acquity UPLC BEH C18 1.7 μm 2.1×50 mmColumn. All the methods are using MeCN/H₂O gradients. MeCN and H₂Ocontain either 0.1% Formic Acid or NH₃ (10 mM). LC-MS columns used:Waters XBridge Prep OBD C18 5 μm 30 mm ID×100 mm L (preparative column)and Waters XBridge BEH C18 5 μm 4.6 mm ID×100 mm L (analytical column).All the methods are using either MeOH/H₂O or MeCN/H₂O gradients. MeOH,MeCN and H₂O contain either 0.1% Formic Acid or 0.1% Diethylamine.Microwave heating was performed with a Biotage Initiator. Celpure® P65is a filtration aid, commercial product (cas number 61790-53-2).

List of abbreviations used in the experimental section:

μL microliter APMA 4-aminophenylmercuric acetate app t Apparent tripletAUC Area Under the Curve BAL Broncho-alveolar lavage BALFBroncho-alveolar lavage fluid bd Broad doublet Boctert-Butyloxy-carbonyl bs Broad singlet BSA Bovine serum albumine btBroad triplet Cat. Catalytic amount cDNA copy deoxyribonucleic acid ddoublet DavePhos 2-Dicyclohexylphosphino-2′- (N,N-dimethylamino)biphenylDCM Dichloromethane DDQ 2,3-Dichloro-5,6-dicyano-1,4- benzoquinone DEADdiethyl azodicarboxylate Desc'd Described in details DIAD Diisopropylazodicarboxylate DIPE Diisopropylether DIPEA N,N-diisopropylethylamineDMA Dimethylacetamide DMF N,N-dimethylformamide DMSO Dimethylsulfoxidedppf 1,1′-Bis(diphenylphosphino)ferrocene EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) EDC•HCl N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride eq. Equivalent Et₂O Diethyl ether EtOAcEthyl acetate EtOH Ethanol FBS Fetal bovine serum FITC FluoresceinIsothiocyanate Fmoc 9-Fluorenylmethoxycarbonyl g gram h hour HOBtHydroxybenzotriazole HPLC High pressure liquid chromatography HRPhorseradish peroxydase Int Intermediate JohnPhos (2-Biphenyl)di-tert-butylphosphine kg kilogram L liter LC-MS Liquid Chromatography-MassSpectrometry LPC lysophosphatidylcholine m multiplet MeCN AcetonitrileMeOH Methanol mg milligram min minute mL millilitre mmol millimoles MMPMatrix Metallo Proteinase MS Ms'd Mass measured by LC-MS MW Molecularweight N.A. Not available NBS N-Bromosuccinimide nBuOH n-Butanol NMRNuclear Magnetic Resonance PBF phosphate buffered formalin PBS Phosphatebuffered saline PCR Polymerase chain reaction Pd(PPh₃)₄Tetrakis(triphenylphosphine)palladium(0) Pd/C Palladium on Carbon 10%Pd₂(dba)₃ Tris(dibenzylideneacetone)dipalladium(0) PdCl₂dppf [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) PEG Polyethyleneglycol ppm part-per-million q quartet QrtPCR quantitative real-time PCRQTL quantitative trait loci r.t. Room temperature RNA Ribonucleic acidRt retention time s singlet sept septuplet t triplet TEA TriethylamineTFA Trifluoroacetic acid THF Tetrahydrofuran TOOS(N-ethyl-N-(2-hydroxy-3- sulfopropyl)-3-methylaniline, sodium saltdihydrate TS Tobacco smoke XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

Synthetic Preparation of the Compounds of the Invention Example 1General Synthetic Methods 1.1. Synthetic Methods Overview

Where R^(y) is halo, NO₂, or —C(═O)Oalkyl, R^(Z) is R⁵ or an alkyl,alkenyl or carbonyl group optionally substituted.Step i: method AStep ii: consists in one of the following methods

B1 (2 steps): Route using isonitrile reagent then reaction with HCOOH

B2 (2 steps): Route using KCN then reaction with HCOOH

Step iii: consists in one of the following methods

C1: Alkylation with NaH as base in DMF

C2: Alkylation with K₂CO₃ as base in acetone

Step iv: consists in one of the following methods

D1: Deformylation under acid conditions

D2: Deformylation under basic conditions

Step v: consists in one of the following methods

E1 (2 steps): formation of thiourea then cyclisation to give thiazolederivative

E2: Aromatic or heteroaromatic nucleophilic substitution

E3 (3 steps): formation of thiourea, methylation, then cyclisation togive oxadiazole derivative

C1: NaH, DMF

Step vi: consists in one or several of the following methods

F1: Buchwald coupling

F2: Suzuki coupling

F3: Negishi coupling

F4: Copper mediated coupling

F5: Boc deprotection

F6: Reduction with (H₂) in presence of transition metal catalyst

F7: Boc protection

F8: Alkylation

F9a and F9b: Amide bond forming reaction

F10: Reductive amination

F11: Sulfonylation

F12a and F12b: Nucleophilic substitution

F13: Saponification

F14: Introduction of hydroxymethyl group

F15: Introduction of trifluoroacetyl group

F16a and F16b: Halogenation

F17: Copper mediated cyanation

F18: Reduction with lithium borohydride

F19: Synthesis of oxazoline

Step vii: consists in one of methods DStep viii: consists in one of methods E or method HStep ix: consists in one of methods CStep x: consists in one or several methods FStep xi: consists in one of methods DStep xii: consists in one or several methods E and F

E1 (2 steps): formation of thiourea then cyclisation to give thiazolederivative

E4: Buchwald coupling

E5 (2 steps): SNAr then Suzuki coupling

Step xiii: consists in one or several methods F

1.2. General Methods 1.2.1. General Method A: Synthesis of IntermediateGen-1

To a solution of amino-pyridine derivative (1 eq.) in MeCN under argonat 0° C. is added NBS (0.5 eq.). The reaction mixture is stirred at r.t.for 1 h then cooled to 0° C. before introducing additional NBS (0.5eq.). The reaction mixture is stirred at r.t. for 1 h then diluted inEtOAc. The organic layer is washed with a saturated NaHCO₃ solution,dried over Na₂SO₄, filtered and concentrated in vacuo. The residue isdiluted in DCM, washed with a 1 M NaOH solution. The organic phase isdried over Na₂SO₄, filtered and concentrated in vacuo to giveIntermediate Gen-1.

1.2.2. Illustrative synthesis of Intermediate Gen-1-a:2-amino-5-bromo-3-fluoropyridine

To a solution of 2-amino-3-fluoro-pyridine (9.4 g, 83.1 mmol, 1 eq.) inMeCN (470 mL) under argon at 0° C. was added NBS (7.4 g, 41.5 mmol, 0.5eq.). The reaction mixture was stirred at r.t. for 1 h then cooled to 0°C. before introducing additional NBS (7.39 g, 41.5 mmol, 0.5 eq.). Thereaction mixture was stirred at r.t. for 1 h then diluted in EtOAc. Theorganic layer was washed with a saturated NaHCO₃ solution, dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was diluted inDCM, washed with a 1 N NaOH solution. The organic phase was dried overNa₂SO₄, filtered and concentrated in vacuo to afford IntermediateGen-1-a (2-amino-5-bromo-3-fluoropyridine).

LC-MS: MW (calcd): 190 (⁷⁹Br), 192 (⁸¹Br); m/z MW. (obsd): 191 (⁷⁹BrM+1), 193 (⁸¹Br M+1).

1.2.3. General Methods B1 and B2: Synthesis of Intermediate Gen-2

1.2.3.1. General Method B1

Step i

To a solution of amino-pyridine derivative Gen-1 (1 eq.) in nBuOH underargon are added successively the aldehyde R^(z)CHO (2.5 eq.), MgCl₂(0.04 eq.) and 1,1,3,3-tetramethylbutyl isocyanide (1.15 eq.). Thereaction mixture is heated at 130° C. for 3.5 h, and then concentratedin vacuo. The residue is partitioned between heptane and water, stirredfor 15 min and filtered on Celpure® P65. The resulting solid is thendissolved with DCM, dried over Na₂SO₄, filtered and concentrated invacuo to afford the expected amine.

Step ii

A solution of the above prepared compound (1 eq.) in formic acid isheated at 80° C. for 1 h. The reaction mixture is concentrated in vacuo.The residue is then triturated in Et₂O. The formed precipitate isfiltered, rinsed and dried to afford Intermediate Gen-2.

1.2.3.2. Illustrative synthesis of Intermediate Gen-2-a:N-(6-Bromo-2-ethyl-8-fluoro-imidazo[1,2-a]pyridin-3-yl)-formamide

Step i

To a solution of 2-amino-3-Fluoro-4-bromo-pyridine (Gen-1-a) (2 g, 10.5mmol, 1 eq.) in nBuOH (12 mL) under argon were added successivelypropionaldehyde (1.9 mL, 26.2 mmol, 2.5 eq.), MgCl₂ (40 mg, 0.42 mmol,0.04 eq.) and 1,1,3,3-tetramethylbutyl isocyanide (2.1 mL, 12 mmol, 1.15eq.). The reaction mixture was heated at 130° C. for 3.5 h, thenconcentrated in vacuo.

The residue was partitioned between heptane (10 mL) and water (20 mL),stirred for 15 min and filtered on Celpure® P65. The resulting solid wasthen dissolved with DCM, dried over Na₂SO₄, filtered and concentrated invacuo to afford the corresponding amine. The filtrate was furtherextracted with DCM, the combined organic layers were washed with water,a 1 M NaOH solution, and brine dried over Na₂SO₄, filtered andconcentrated in vacuo to deliver a second batch of the expected amine.

¹H NMR δ (ppm) (400 MHz, CDCl₃): 8.11 (1H, s), 6.90 (1H, d), 2.85-2.80(1H, m), 2.76 (2H, q), 1.67 (2H, s), 1.37 (3H, t), 1.16 (6H, s), 1.11(9H, s).

LC-MS: MW (calcd): 369 (⁷⁹Br), 371 (⁸¹Br); m/z MW. (obsd): 370 (⁷⁹BrM+1), 372 (⁸¹Br M+1).

Step ii

A solution of amine (2.9 g, 7.83 mmol, 1 eq.) in formic acid (23 mL) washeated at 80° C. for 1 h. The reaction mixture was then concentrated invacuo. The residue was triturated in toluene and evaporated twice. Theresulting solid was taken up in Et₂O, stirred for 45 min, then filtered,rinsed and dried to afford Intermediate Gen-2-a.

¹H NMR δ (ppm) (400 MHz, CDCl₃): 2 rotamers 8.55 (1H, s), 8.15 (1H, d),7.95 (1H, s), 7.76 (1H, s), 7.54-7.44 (1H, m), 7.13-6.96 (3H, m), 2.80(2H, q), 2.74 (2H, q), 1.33 (3H, t), 1.31 (3H, t).

LC-MS: MW (calcd): 285 (⁷⁹Br), 287 (⁸¹Br); m/z MW. (obsd): 286 (⁷⁹BrM+1), 288 (⁸¹Br M+1).

1.2.3.3. General Method B2

Step i

To a suspension of amino-pyridine derivative Gen-1 (1 eq.) in tolueneare added the aldehyde R^(z)CHO (1 eq.) and benzotriazole (1 eq.). Themixture is stirred at r.t. overnight. Additional aldehyde reagent (0.06eq.) and benzotriazole (0.06 eq.) are added. After 4 h stirring,potassium cyanide (1.2 eq.) is added, followed by EtOH. The reactionmixture is stirred at r.t. for 5 days. The crude product mixture is thenquenched with a 3 M NaOH solution. Solvents are evaporated carefully invacuo. The residue is diluted with water and EtOAc. The aqueous layer isextracted with EtOAc. The combined organic layers are washed with waterand brine, dried over Na₂SO₄ and concentrated in vacuo. The crudeproduct mixture is dissolved in EtOH and carefully added to a solutionof acetyl chloride (2.1 eq.) in EtOH at 0° C. The resulting reactionmixture is stirred at r.t. overnight and then concentrated to dryness toafford the corresponding imidazo[1,2-a]pyridin-3-ylamine ashydrochloride salt.

Step ii

A solution of the above prepared imidazo[1,2-a]pyridin-3-ylaminehydrochloride salt (1 eq.) in formic acid is heated at 90° C. for 2 h.Solvents are evaporated in vacuo. The residue is dissolved in water. Themixture is carefully basified with a saturated NaHCO₃ solution until pH8-9 is reached. The formed solid is filtered, washed with water and DIPEand dried to afford Intermediate Gen-2.

1.2.3.4. Illustrative synthesis of Intermediate Gen-2-d:N-(6-Bromo-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-3-yl)-formamide

Step i

To a suspension of 2-amino-5-bromo-3-methylpyridine (420 g, 2.24 mol, 1eq.) previously washed with a saturated NaHCO₃ solution before use in1.5 L of toluene under nitrogen were added propionaldehyde (248 mL, 3.36mol, 1.5 eq.) and 1H-benzotriazole (281 g, 2.36 mol, 1.05 eq.). Theresulting mixture was stirred 4 h at r.t. before adding 3.5 L of EtOHand potassium cyanide (175 g, 2.70 mol, 1.2 eq.). The reaction mixturewas further stirred overnight at r.t. and 2 h at 78° C. After cooling tor.t., the mixture was quenched by addition of a 2.5 M NaOH solution (3L).

This experiment was performed in four batches with the same quantitiesof reagents, the crude mixture were then pooled together andconcentrated in vacuo. The remaining oil was diluted with EtOAc (15 L)and washed with a 2 M NaOH solution (2×2 L). The aqueous layer wasextracted twice with EtOAc (2×1 L). The combined organic layers werethen dried over Na₂SO₄, filtered and concentrated in vacuo. The crudemixture was dissolved in EtOH (2 L) and carefully added to a solution ofacetyl chloride (1 L, 14.0 mol, 1.6 eq.) in EtOH (6 L). The resultingreaction mixture was stirred at r.t. overnight and then concentrated todryness. The residue was triturated in DCM (7 L) for 3 days, theprecipitate formed was collected, washed with DCM (2×500 mL) and driedto afford 6-Bromo-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-3-ylamine as ahydrochloride salt.

¹H NMR δ (ppm) (400 MHz, DMSO): 8.70 (1H, s), 7.75 (1H, s), 4.86 (3H,bs), 2.81 (2H, q), 2.56 (3H, s), 1.56 (3H, s).

LC-MS: MW (calcd): 253 (⁷⁹Br), 255 (⁸¹Br); m/z MW. (obsd): 254 (⁷⁹BrM+1), 256 (⁸¹Br M+1).

Step ii

A suspension of the above prepared6-bromo-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-3-ylamine hydrochloride(785 g, 2.70 mol, 1 eq.) in formic acid (713 mL, 18.9 mol, 7 eq.) washeated to 80° C. for 2 h. The crude mixture was concentrated in vacuo tolow volume (about 400 mL). The residue was brought up in water (1 L) anda 3 M solution of NaOH (2 L), and further basified with a saturatedNaHCO₃ solution until foaming ceased and pH reached 8-9. Afterhomogenization for 1 h, the precipitate was filtered and washed withwater (2×300 mL). Purification was achieved by dissolution in a mixtureof toluene and MeOH 3:1 (4 L) followed by concentration in vacuo.Trituration of the residue in a mixture of 200 mL of MeOH and 5 L ofDIPE, decantation and filtration of the resulting suspension affordedN-(6-bromo-2-ethyl-8-methylimidazo[1,2-a]pyridin-3-yl)formamide(Intermediate Gen-2-d).

Rotamer A: ¹H NMR δ (ppm) (400 MHz, DMSO): 10.2 (1H, bs), 8.36 (1H, s),8.11 (1H, s), 7.21 (1H, s), 2.63-2.60 (2H, m), 2.56 (3H, s), 1.24-1.17(3H, m)

Rotamer B: ¹H NMR δ (ppm) (400 MHz, DMSO): 8.51 (1H, s), 8.23 (1H, s),8.11 (1H, s), 7.23 (1H, s), 2.63-2.60 (2H, m), 2.58 (3H, s), 1.24-1.17(3H, m)

LC-MS: MW (calcd): 281 (⁷⁹Br), 283 (⁸¹Br); m/z MW. (obsd): 282 (⁷⁹BrM+1), 284 (⁸¹Br M+1).

1.2.4. General Methods C1 and C2: Synthesis of Intermediate Gen-3

1.2.4.1. General Method C1

To a solution of imidazo[1,2-a]pyridine-3-ylamine derivative (1 eq.) inDMF is added NaH (1.5 eq.) portionwise, then alkyl iodide (1.4 eq.). Thereaction mixture is stirred for 1 h then quenched with water and dilutedwith EtOAc. The aqueous layer is extracted with EtOAc. The combinedorganic layers are washed with water and brine, dried over Na₂SO₄ andconcentrated in vacuo. The residue is triturated with DIPE. The solid isfiltered, rinsed with DIPE and dried to give the expected intermediate.

1.2.4.2. Illustrative synthesis of Intermediate Gen3-b:N-(6-bromo-2-ethylimidazo[1,2-a]pyridin-3-yl)-N-methylformamide

NaH (60% suspension in oil, 151 g, 3.76 mol, 1.5 eq.) was addedportionwise at r.t. over a period of 30 min. to a solution ofIntermediate Gen-2-b (673 g, 2.51 mol, 1 eq.) in DMF (6 L). The internaltemperature increased to 35° C. during the addition and the reactionmixture was directly cooled to 15° C. Methyl iodide (502 g, 3.53 mol,1.4 eq.) was added dropwise over a period of 1 h. The reaction mixturewas kept below 20° C., stirred for 1 h then quenched with water (220mL). Solvents were evaporated in vacuo. The residue was diluted withwater (3 L) and EtOAc (4 L). The aqueous layer was extracted with EtOAc(3×1 L). The combined organic layers were washed with water (2×3 L) andbrine (1.5 L), dried over Na₂SO₄ and concentrated in vacuo. The residuewas triturated with DIPE (2 L). The solids were filtered, rinsed withDIPE (2×1 L) and dried to give Intermediate Gen3-b.

¹H NMR δ (ppm) (400 MHz, CDCl₃): 7.92 (1H, s), 7.78 (1H, s), 7.33 (1H,d), 7.30 (1H, d), 3.25 (3H, s), 2.72 (2H, q), 1.35 (3H, t).

LC-MS: MW (calcd): 281 (⁷⁹Br), 283 (⁸¹Br); m/z MW. (obsd): 284 (⁸¹BrM+1).

1.2.4.3. General Method C2

To a suspension of imidazo[1,2-a]pyridine-3-ylamine derivative (1 eq.)in acetone are added potassium carbonate (3 eq.) and alkyl iodide (1.5eq. to 1.9 eq.). The reaction mixture is stirred at a temperaturecomprised between r.t. and refluxing temperature. If after stirringovernight, the reaction is not complete, additional alkyl iodide (0.07eq.) is then introduced and stirring is continued for 1 h. The reactionmixture is filtered and washed with acetone and DCM. The filtrate isconcentrated in vacuo and the residue is partitioned between DCM andwater. The aqueous layer is further extracted with DCM. The combinedorganic layers are then washed with brine, dried over Na₂SO₄, filteredand concentrated in vacuo. The solid is triturated with Et₂O at r.t. for1 h, filtered off and dried to afford the expected Intermediate.

1.2.4.4. Illustrative synthesis of Intermediate Gen-3-e:N-(6-bromo-2-ethyl-8-methylimidazo[1,2-a]pyridin-3-yl)-N-methylformamide

To a suspension of formamide Gen-2-d (720 g, 2.55 mol, 1 eq.) in 5 L ofacetone were added potassium carbonate (1 kg, 7.66 mol, 3 eq.) andmethyl iodide (700 g, 4.93 mol, 1.9 eq.). The reaction mixture washeated to 40° C. overnight. Additional methyl iodide (25 g, 0.18 mol,0.07 eq.) was then introduced and stirring continued for 1 h at 40° C.The reaction mixture was filtered and washed with acetone (2×300 mL) andDCM (2×300 mL). The filtrate was concentrated in vacuo and the residuewas partitioned between DCM (3 L) and water (1 L). The aqueous layer wasfurther extracted with DCM. The combined organic layers were then washedwith brine, dried over Na₂SO₄, filtered and concentrated in vacuo. Thesolid was triturated with Et₂O (1 L) at r.t. for 1 h, filtered off anddried to afford Intermediate Gen-3-e.

Rotamer A (Major): ¹H NMR δ (ppm) (400 MHz, CDCl₃): 8.19 (1H, s), 7.78(1H, s), 7.15 (1H, s), 3.24 (3H, s), 2.72 (2H, q), 2.59 (3H, s), 1.31(3H, t)

Rotamer B (Minor): ¹H NMR δ (ppm) (400 MHz, CDCl₃): 8.49 (1H, s), 7.65(1H, s), 7.08 (1H, s), 3.36 (3H, s), 2.72 (2H, q), 2.59 (3H, s), 1.31(3H, t)

LC-MS: MW (calcd): 295 (⁷⁹Br), 297 (⁸¹Br); m/z MW. (obsd): 296 (⁷⁹BrM+1), 298 (⁸¹Br M+1).

1.2.5. General Methods D1 and D2: Synthesis of Intermediate Gen-4

1.2.5.1. General Method D1

A 4 M HCl solution in dioxane or 1.25 M HCl solution in MeOH (9 eq.) isadded to a solution of imidazo[1,2-a]pyridine-3-yl formamide derivative(1 eq.) in MeOH. The reaction mixture is stirred at a room temperatureor refluxed for 3 h. Additional 4 M HCl solution (1.5 eq.) is added andstirring is continued until completion of the reaction. The reactionmixture is then concentrated in vacuo to afford the expectedintermediate.

1.2.5.2. Illustrative synthesis of Intermediate Gen-4-d:(6-Bromo-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-3-yl)-methyl-amine

Intermediate Gen-3-e (80 g, 270 mmol, 1 eq.) was dissolved in a 1.25 MHCl solution in MeOH (540 mL, 2.5 eq.) and the resulting mixture wasrefluxed overnight. 270 mL of 1.25 M HCl solution in MeOH were added andheating continued overnight. After 48 h, additional 70 mL of the 1.25 MHCl solution in MeOH were introduced in the reaction mixture. Heatingwas maintained overnight until conversion was complete. The crudemixture was then concentrated in vacuo and the residue was partitionedbetween EtOAc (300 mL) and water (700 mL). A saturated NaHCO₃ solutionwas added until pH reached 8-9. The aqueous layer was extracted twicewith EtOAc (2×300 mL). The combined organic layers were then washed withbrine (200 mL), dried over Na₂SO₄, filtered and concentrated in vacuo togive Intermediate Gen-4-d(6-bromo-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-3-yl)-methyl-amine) as afree base.

¹H NMR δ (ppm) (400 MHz, CDCl₃): 8.05 (1H, s), 7.04 (1H, s), 2.84-2.78(5H, m), 2.60 (3H, s), 1.35 (3H, t)

LC-MS: MW (calcd): 267 (⁷⁹Br), 269 (⁸¹Br); m/z MW. (obsd): 268 (⁷⁹BrM+1), 270 (⁸¹Br M+1).

1.2.5.3. General Method D2

A 10 M aqueous KOH solution (15 eq.) is added to a solution ofimidazo[1,2-a]pyridine-3-yl formamide derivative (1 eq.) in MeOH. Thereaction mixture is stirred at r.t. for 3 h, then quenched with brineand MeOH is removed in vacuo. The remaining aqueous phase is extractedwith DCM three times. The combined organic layers are washed with brine,dried over MgSO₄, filtered and concentrated in vacuo to afford theexpected intermediate as a free base.

1.2.5.4. Illustrative synthesis of Intermediate Gen-4-a:(6-Bromo-2-ethyl-8-fluoro-imidazo[1,2-a]pyridin-3-yl)-methyl-amine

A 10 M aqueous KOH solution (25 mL, 250 mmol, 15 eq.) was added to asolution of imidazo-pyridine Intermediate Gen-3-a (5 g, 16.67 mmol, 1eq.) in 25 mL of MeOH. The reaction mixture was stirred at r.t. for 3 h,then quenched with brine and MeOH was removed in vacuo. The remainingaqueous phase was extracted with DCM three times. The combined organiclayers were washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo to afford Intermediate Gen-4-a as a free base.

LC-MS: MW (calcd): 271 (⁷⁹Br), 273 (⁸¹Br); m/z. (obsd): 272 (⁷⁹Br M+1),274 (⁸¹Br M+1).

1.2.6. General Methods E1, E2, E3 and C: Synthesis of Intermediate Gen-5

1.2.6.1. General Method E1

Step i

To a suspension of imidazo[1,2-a]pyridine-3-ylamine derivative (1 eq.)in DCM is added TEA (4.5 eq.). The mixture is stirred for 30 min at r.t.then Fmoc-isothiocyanate (1.3 eq.) is added. The resulting solution isstirred at r.t. for 3 h. Piperidine (3.2 eq.) is then introduced and thereaction mixture is stirred at r.t. overnight. Water is added to thesolution and the layers are separated. The aqueous layer is extractedwith DCM/MeOH. The combined organic layers are washed with brine, driedover Na₂SO₄ and concentrated in vacuo. The expected product is obtainedeither by chromatography on silica gel or crystallization to afford thecorresponding thiourea.

Step ii

The above prepared thiourea (1 eq.) is added to a solution of thecorresponding bromo acetophenone Gen-11 or commercial product (1.3 eq.)in EtOH. The reaction mixture is stirred at reflux for 3 h thenconcentrated in vacuo. The crude product is triturated in hot EtOAc andstirred for 30 min, allowed to cool to r.t., filtered off and rinsedwith EtOAc to afford the expected Intermediate Gen-5.

1.2.6.2. Illustrative synthesis of Intermediate Gen-5-b:(6-Bromo-2-ethyl-imidazo[1,2-a]pyridin-3-yl)-[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amine

Step i

To a suspension of Intermediate Gen-4-b (170 g, 520 mmol, 1 eq.) in DCM(3 L), was added triethylamine (325 mL, 2.34 mol, 4.5 eq.). The mixturewas stirred for 30 min at r.t. then Fmoc-isothiocyanate (190 g, 676mmol, 1.3 eq.) was added. The formed solution was stirred at r.t. for 3h. Piperidine (164 mL, 1.66 mol, 3.2 eq.) was added to the solution andthe reaction mixture was stirred at r.t. overnight. Water (1.5 L) wasadded to the solution and the layers were separated. The aqueous layerwas extracted with DCM/MeOH. The combined organic layers were washedwith brine, dried over Na₂SO₄ and concentrated in vacuo. The residue wastriturated with MeCN, filtered and rinsed with MeCN and Et₂O to affordthe corresponding thiourea.

¹H NMR δ (ppm) (400 MHz, CDCl₃): 7.88 (1H, s), 7.32 (1H, d), 7.30 (1H,d), 3.67 (3H, s), 2.75 (2H, q), 1.33 (3H, t).

LC-MS: MW (calcd): 312 (⁷⁹Br), 314 (⁸¹Br); m/z MW. (obsd): 313 (⁷⁹BrM+1), 315 (⁸¹Br M+1).

Step ii

The above prepared thiourea (62.5 g, 180 mmol, 1 eq.) was added to asolution of 2-bromo-4′-fluoroacetophenone (50.7 g, 233 mmol, 1.3 eq.) inEtOH (1.5 L). The reaction mixture was stirred at reflux for 3 h thenconcentrated in vacuo. The crude product was triturated in hot EtOAc andstirred for 30 min, allowed to cool to r.t., filtered off and rinsedwith EtOAc to afford Intermediate Gen-5-b.

¹H NMR δ (ppm) (400 MHz, MeOD): 8.75 (1H, s), 7.98 (2H, dd), 7.83-7.75(3H, m), 7.14-7.03 (3H, m), 3.63 (3H, s), 2.86 (2H, q), 1.36 (3H, t).

LC-MS: MW (calcd): 430 (⁷⁹Br), 432 (⁸¹Br); m/z MW. (obsd): 431 (⁷⁹BrM+1), 433 (⁸¹Br M+1).

1.2.6.3. General Method E2

To a solution of imidazo[1,2-a]pyridine-3-ylamine derivative (1 eq.) andthe halogeno heteroaryl derivative (1.2 eq.) in THF under argon is addedNaH (3 eq.). The reaction mixture is heated at 90° C. overnight. Aftercooling to r.t. the mixture is slowly quenched by addition of water andthen diluted with EtOAc. The organic layer is separated and the aqueouslayer extracted with EtOAc. The combined organic layers are washed withwater and brine, dried over Na₂SO₄, filtered and concentrated in vacuo.The residue is purified either by chromatography on silica gel or bycrystallization to deliver the expected intermediate.

1.2.6.4. Illustrative synthesis of Intermediate Gen-5-t:2-[(6-Bromo-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-3-yl)-methyl-amino]-4-(4-fluoro-phenyl)-thiazole-5-carbonitrile

To a solution of amine Gen-4-d (4.4 g, 16.6 mmol, 1 eq.) in THF (44 mL)under argon was slowly added NaH (60% in oil suspension, 2.0 g, 50.0mmol, 3 eq.). The reaction mixture was heated at 90° C. for 30 min thencooled to 40° C. before adding the chlorothiazole Gen-12-a (4.74 g, 19.9mmol, 1.2 eq.). The reaction mixture was stirred at 90° C. overnight.After cooling to r.t. the mixture was slowly quenched by addition ofwater and then diluted with EtOAc. The organic layer was separated andthe aqueous layer extracted with EtOAc. The combined organic layers werethen washed with water and brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was triturated in Et₂O, filtered andwashed with Et₂O and MeCN. Recrystallization was performed in MeCN (180mL) to afford Intermediate Gen-5-t(2-[(6-Bromo-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-3-yl)-methyl-amino]-4-(4-fluoro-phenyl)-thiazole-5-carbonitrile).

¹H NMR δ (ppm) (400 MHz, CDCl₃): 8.15 (2H, dd), 7.80 (1H, s), 7.22-7.14(3H, m), 3.62 (3H, s), 2.77 (2H, q), 2.64 (3H, s), 1.35 (3H, t)

LC-MS: MW (calcd): 469 (⁷⁹Br), 471 (⁸¹Br); m/z MW. (obsd): 470 (⁷⁹BrM+1), 472 (⁸¹Br M+1).

1.2.6.5. General Method E3

Step i

To a suspension of imidazo[1,2-a]pyridine-3-ylamine derivative (1 eq.)in DCM is added TEA (4.5 eq.). The mixture is stirred until dissolved atr.t. then Fmoc-isothiocyanate (2.2 eq.) is added. The resulting solutionis stirred at r.t. overnight. Piperidine (5 eq.) is then introduced andthe reaction mixture is stirred at r.t. for 4 h. Water is added to thesolution and the layers are separated. The aqueous layer is extractedwith DCM. The combined organic layers are washed with brine, dried overNa₂SO₄ and concentrated in vacuo to give the expected thiourea.

Step ii

The above prepared thiourea (1 eq.) is dissolved in acetone and MeOH,NaHCO₃ (1 eq.) and MeI (6 eq.) are added, the reaction mixture isstirred at 60° C. for 3 h. Then the reaction mixture is stirred at r.t.over 2 d. Then the reaction mixture is concentrated in vacuo, theresidue is dissolved in a mixture of DCM and MeOH. Solids are filteredoff, and the filtrate is concentrated in vacuo. The residue is purifiedby chromatography on silica gel (elution with DCM/MeOH: 100/0 to 90/10)to afford the expected methylthiourea.

Step iii

TEA (3 eq.) is added to a solution of the above prepared methylthiourea(1 eq.) in EtOH, followed by the arylamidoxime derivative (2 eq.), thenthe reaction mixture is stirred at 80° C. over 2 d. The reaction mixtureis quenched by addition of a saturated NaHCO₃ solution and extractedwith DCM three times. The organic phases are combined, dried over Na₂SO₄and concentrated in vacuo. The residue is purified by chromatography onsilica gel to afford the expected intermediate.

1.2.6.6. Illustrative synthesis of Intermediate Gen-5-ae:(6-Bromo-2-ethyl-imidazo[1,2-a]pyridin-3-yl)-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-methyl-amine

Step i

To a suspension of the hydrochloride salt of Gen-4-b (11.6 g, 35.5 mmol,1 eq.) in 250 mL of DCM was added TEA (20.49 mL, 147.1 mmol, 4.5 eq.).The mixture was stirred at r.t. until full dissolution occurred, thenFmoc-isothiocyanate (21.95 g, 74.5 mmol, 2.2 eq.) was added. Theresulting solution was stirred at r.t. overnight. Piperidine (17.52 mL,177.0 mmol, 5 eq.) was then introduced and the reaction mixture wasstirred at r.t. for 4 h. Water was added to the solution and the layerswere separated. The aqueous layer was extracted with DCM. The combinedorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to give the expected thiourea.

Step ii

The above prepared thiourea (500 mg, 1.59 mmol, 1 eq.) was dissolved in150 mL of acetone and 30 mL of MeOH, NaHCO₃ (134 mg, 1.59 mmol, 1 eq.)and MeI (1.36 g, 9.58 mmol, 6 eq.) were added, the reaction mixture isstirred at 60° C. for 3 h. Then the reaction mixture was stirred at r.t.over 2 d. The reaction mixture was then concentrated in vacuo, and theresidue was dissolved in a mixture of DCM and MeOH (9/1). Solids werefiltered off, and the filtrate was concentrated in vacuo. The residuewas purified by chromatography on silica gel (elution with DCM/MeOH:100/0 to 90/10) to afford the expected methylthiourea.

LC-MS: MW (calcd): 326 (⁷⁹Br), 328 (⁸¹Br); m/z. (obsd): 327 (⁷⁹Br M+1),329 (⁸¹Br M+1).

Step iii

TEA (0.383 mL, 2.75 mmol, 3 eq.) was added to a solution of the aboveprepared methylthiourea (300 mg, 0.917 mmol, 1 eq.) in 10 mL of EtOH,followed by 4-fluorobenzamidoxime (283 mg, 1.833 mmol, 2 eq.), then thereaction mixture was stirred at 80° C. over 2 days. The reaction mixturewas quenched by addition of a saturated NaHCO₃ solution (100 mL) andextracted with 20 mL of DCM three times. The organic phases werecombined, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by chromatography on silica gel (elution with DCM/MeOH: 100/0to 95/5) to afford Intermediate Gen-5-ae.

LC-MS: MW (calcd): 415 (⁷⁹Br), 417 (⁸¹Br); m/z. (obsd): 416 (⁷⁹Br M+1),418 (⁸¹Br M+1).

1.2.6.7. General Method C1

Intermediates Gen-5 are prepared from intermediates Gen-7 according togeneral method C1 described previously

1.2.7. General Methods F, E1, E4 and E5: Synthesis of IntermediateGen-10

1.2.7.1. General Method F1

1.2.7.1.1. General Method F1a

To a solution of the 6-halo-imidazo[1,2-a]pyridine-3-ylamine derivative(1 eq.) in toluene under argon are successively added the correspondingamine (5 eq.), sodium tert-butoxide (2 eq.), and then ligand (0.13 eq.)and palladium catalyst (0.1 eq.). The reaction mixture is heated at 115°C. until completion. After cooling to r.t., the crude product isfiltered on Celpure® P65, the residue is washed with EtOAc and thefiltrate is then concentrated in vacuo. The crude product is purified bychromatography on silica gel to afford the expected intermediate.

1.2.7.1.2. Illustrative synthesis of Intermediate Gen-10-i:2-((2-ethyl-6-(piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino-4-(4-fluorophenyl)thiazole-5-carbonitrile

To a solution of bromide Gen-5-e (300 mg, 0.66 mmol, 1 eq.) in toluene(6 mL) under argon were successively added piperazine (283 mg, 3.28mmol, 5 eq.), sodium tert-butoxide (126 mg, 1.31 mmol, 2 eq.), and thenJohnPhos (26 mg, 0.085 mmol, 0.13 eq.) and Pd₂(dba)₃ (60 mg, 0.065 mmol,0.1 eq.). The reaction mixture was heated at 115° C. for 45 min. Aftercooling to r.t., the crude product was filtered on Celpure® P65, theresidue was washed with EtOAc and the filtrate was then concentrated invacuo. The crude product was purified by chromatography on silica gel(elution with DCM/MeOH/7 N NH₃ in MeOH: 100/0/0 to 100/8/1) to affordIntermediate Gen-10-i.

¹H NMR δ (ppm) (400 MHz, CDCl₃): 8.08 (1H, dd), 7.50 (1H, d), 7.46-7.31(2H, m), 7.21-7.11 (3H, m), 3.61 (3H, s), 3.06 (8H, bs), 2.73 (2H, q),1.33 (3H, t).

LC-MS: MW (calcd): 461; m/z MW. (obsd): 462 (M+1).

1.2.7.1.3. General Method F1 b

To a solution of the 6-halo-imidazo[1,2-a]pyridine-3-ylamine derivative(1 eq.) in toluene under argon are successively added the correspondingamine (1.1 to 1.5 eq.), sodium tert-butoxide (1.18 to 2 eq.), and thenJohnPhos, XantPhos or DavePhos (0.06 to 0.1 eq.) and Pd₂(dba)₃ (0.02 to0.05 eq.). The reaction mixture is heated at 115° C. until completion.After cooling to r.t., the crude product is filtered on Celpure® P65,the residue is washed with EtOAc and the filtrate concentrated in vacuo.The crude product is purified by chromatography on silica gel to affordthe expected intermediate.

1.2.7.1.4. Illustrative synthesis of4-(3-{[5-Cyano-4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-6-yl)-piperazine-1-carboxylicacid tert-butyl ester

To a solution of Intermediate Gen-5-t (24.2 g, 51.5 mmol, 1 eq.) intoluene under argon were successively added N-Boc piperazine (14.4 g,77.3 mmol, 1.5 eq.), sodium tert-butoxide (9.9 g, 103 mmol, 2 eq.),JohnPhos (1.54 g, 5.15 mmol, 0.1 eq.) and Pd₂(dba)₃ (2.36 g, 2.58 mmol,0.05 eq.). The reaction mixture was heated at 115° C. for 1 h. Aftercooling to r.t., the crude product was filtered on Celpure® P65 and theresidue dissolved in EtOAc and washed with water. The organic layer wasfurther washed with brine, dried over Na₂SO₄, filtered and concentratedin vacuo. The crude product was purified by chromatography on silica gel(elution with heptane/EtOAc: 90/10 to 20/80) to afford the expectedproduct.

¹H NMR δ (ppm) (400 MHz, CDCl₃): 8.16 (2H, dd), 7.17 (2H, app t), 6.99(2H, bs), 3.62-3.53 (4H, m), 3.60 (3H, s), 3.04-2.93 (4H, m), 2.74 (2H,q), 2.62 (3H, s), 1.47 (9H, s), 1.33 (3H, t).

LC-MS: MW (calcd): 575; m/z MW. (obsd): 576 (M+1).

1.2.7.2. General Method F2

To a solution of the bromide Gen-5-b (21.6 g, 45.1 mmol, 1 eq.) in amixture dioxane/water (300 mL/75 mL) under argon were successively addedsodium carbonate (14.3 g, 135 mmol, 3 eq.), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (18.1 g, 58.6 mmol, 1.3eq.), and then Pd(PPh₃)₄ (3.91 g, 3.38 mmol, 0.075 eq.). The reactionmixture was heated at 85° C. for 3 h. After cooling to r.t., the crudeproduct is filtered on Clarcel and the filtrate is concentrated invacuo. The residue is purified by chromatography on silica gel to affordthe expected intermediate.

1.2.7.3. Illustrative synthesis of4-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-a]pyridin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

To a solution of the bromide Gen-5-b (21.6 g, 45.1 mmol, 1 eq.) in adioxane/water (300 mL/75 mL) mixture under argon were successively addedsodium carbonate (14.3 g, 135 mmol, 3 eq.), the corresponding boronicester (18.1 g, 58.6 mmol, 1.3 eq.), and then Pd(PPh₃)₄ (3.91 g, 3.38mmol, 0.075 eq.). The reaction mixture was heated at 85° C. for 3 huntil completion. After cooling to r.t., the reaction mixture wasconcentrated in vacuo. The crude product was partitioned between EtOAcand water. The aqueous layer was extracted twice with EtOAc. Thecombined organic layers were then washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was then purified bychromatography on silica gel (elution with DCM/MeOH 100/0 to 97/3) toafford the expected compound.

LC-MS: MW (calcd): 533; m/z MW. (obsd): 534 (M+1).

1.2.7.4. General Method F3

To a solution of the 6-halo-imidazo[1,2-a]pyridine-3-ylamine derivative(1 eq.) in DMA under argon are successively added the copper iodide(0.25 eq.), PdCl₂dppf (0.1 eq.), and a solution of the correspondingorganozinc compound (1.3 eq.) in DMA. The reaction mixture is heated at80° C. for 3 h then additional solution of the corresponding organozinccompound (0.6 eq.) in DMA is added. Stirring at 80° C. is continuedovernight. After cooling to r.t., the crude product is filtered onCelpure® P65, the residue is washed with EtOAc and the filtrate iswashed with water and brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product is purified by chromatographyon silica gel to afford the expected intermediate.

1.2.7.5. Illustrative synthesis of4-(3-{[5-Cyano-4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-6-yl)-piperidine-1-carboxylicacid tert-butyl ester

To a solution of the bromide Gen-5-t (600 mg, 1.28 mmol, 1 eq.) in DMA(4.4 mL) under argon were successively added the copper iodide (61 mg,0.32 mmol, 0.25 eq.), PdCl₂dppf (93 mg, 0.13 mmol, 0.1 eq.), and asolution of the corresponding organozinc compound (prepared from4-iodo-Boc-piperidine (Corley, et al., 2004)) in DMA (1 M in DMA, 1.66mL, 1.66 mmol, 1.3 eq.). The reaction mixture was heated at 80° C. for 3h then additional solution of the corresponding organozinc compound (0.5mL, 0.5 mmol, 0.6 eq.) in DMA was added. Stirring at 80° C. wascontinued overnight. After cooling to r.t., the crude product wasfiltered on Celpure® P65, the residue was washed with EtOAc and thefiltrate washed with water and brine, dried over Na₂SO₄ and concentratedin vacuo. The crude product was purified by chromatography on silica gel(elution heptanes/EtOAc 100/0 to 50/50) to deliver the expectedcompound.

LC-MS: MW (calcd): 574; m/z MW. (obsd): 575 (M+1).

1.2.7.6. General Method F4

To a suspension of 6-halo-imidazo[1,2-a]pyridine-3-ylamine derivative (1eq.), potassium carbonate (2 to 3 eq.), the corresponding amine (1.2 to2 eq.), and CuI (0.1 to 0.2 eq.) in DMF under argon, is added thetrans-1,2-diaminocyclohexane (0.2 to 0.4 eq.), and then the reactionmixture is heated between 85° C. and 100° C. overnight. After cooling tor.t., the crude product is filtered on Celite, and the residue is washedwith EtOAc. The filtrate is washed with a saturated NaHCO₃ solution, thetwo phases are separated, and the aqueous phase is washed twice withEtOAc. The combined organic layers are washed with brine, dried overNa₂SO₄, filtered and concentrated in vacuo. The crude product ispurified by chromatography on silica gel to afford the expectedintermediate.

1.2.7.7. Illustrative synthesis of compound 62:4-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-a]pyridin-6-yl)-3-oxo-piperazine-1-carboxylicacid tert-butyl est

To a suspension of Gen-5-b (600 mg, 1.391 mmol, 1 eq.), potassiumcarbonate (577 mg, 4.173 mmol, 3 eq.), 3-oxo-piperazine-1-carboxylicacid tert-butyl ester (557 mg, 2.78 mmol, 2 eq.), and CuI (53 mg, 0.278mmol, 0.2 eq.) in DMF (4 mL) under argon, was added the1,2-diaminocyclohexane (67 μL, 0.56 mmol, 0.4 eq.), and then thereaction mixture was heated at 100° C. overnight. After cooling to r.t.,the crude product was filtered on Celite, and the residue was washedwith EtOAc. The filtrate was washed with a saturated NaHCO₃ solution,the two phases were separated, and the aqueous phase was washed twicewith EtOAc. The combined organic layers were washed with brine, driedover Na₂SO₄, filtered and concentrated in vacuo. The crude product waspurified by chromatography on silica gel to afford the expectedcompound.

LC-MS: MW (calcd): 550; m/z MW. (obsd): 551 (M+1).

1.2.7.8. General Method F5 (Boc Removal)

1.2.7.8.1. General Method F5a

To a solution of the boc protected amine (1 eq.) in DCM is added TFA (10eq.). The reaction mixture is stirred at r.t. until completion. Then thereaction mixture is partitioned between DCM and water. The aqueous layeris washed twice with DCM. A saturated Na₂CO₃ solution is added to theaqueous layer until pH reached 8-9 and is extracted with DCM twice. Thecombined organic layers are then washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo to afford the expected intermediate

1.2.7.8.2. Illustrative synthesis of Compound 177:[6-(3-Amino-azetidin-1-yl)-2-ethyl-imidazo[1,2-a]pyridin-3-yl]-[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amine

[1-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-a]pyridin-6-yl)-azetidin-3-yl]-carbamicacid tert-butyl ester was prepared from intermediate Gen-5-b and3-N-Boc-amino-azetidine using method F1b. To a solution of this compound[(200 mg, 0.383 mmol, 1 eq.) in DCM (3 mL) was added TFA (291 μL, 3.827mmol, 10 eq.). The reaction mixture was stirred at r.t. for 2.5 days,then the reaction mixture was partitioned between DCM and water. Theaqueous layer was washed twice with DCM. A saturated Na₂CO₃ solution wasadded to the aqueous layer until pH reached 8-9 and was extracted withDCM twice. The combined organic layers were then washed with brine,dried over Na₂SO₄, filtered and concentrated in vacuo to afford theexpected compound.

LC-MS: MW (calcd): 422; m/z MW. (obsd): 423 (M+1).

1.2.7.8.3. General Method F5b

To a solution of the boc protected amine (1 eq.) in MeOH is added a 2 NHCl solution in Et₂O or 4 M HCl solution in dioxane or 1.25 M HClsolution in MeOH (6 eq.). The reaction mixture is stirred at r.t. untilcompletion then concentrated in vacuo. The residue is partitionedbetween EtOAc and water. The aqueous layer is extracted twice withEtOAc. A 2 N NaOH solution is added to the aqueous layer until pHreached 8-9 and further extraction with EtOAc is performed. The combinedorganic layers are then washed with brine, dried over Na₂SO₄, filteredand concentrated in vacuo to afford the Intermediate Gen-10.

1.2.7.8.4. Illustrative synthesis of Compound 1:2-[(2-Ethyl-8-methyl-6-piperazin-1-yl-imidazo[1,2-a]pyridin-3-yl)-methyl-amino]-4-(4-fluoro-phenyl)-thiazole-5-carbonitrile

4-(3-{[5-Cyano-4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-6-yl)-piperazine-1-carboxylicacid tert-butyl ester was prepared from intermediate Gen-5-t usingBoc-piperazine and method F1b.

To a solution of4-(3-{[5-Cyano-4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-6-yl)-piperazine-1-carboxylicacid tert-butyl ester (24.4 g, 42 mmol, 1 eq.) in MeOH (100 mL) wasadded a 2 M HCl solution in Et₂O (127 mL, 254 mmol, 6 eq.). The reactionmixture was stirred at r.t. for 3.5 h then concentrated in vacuo. Theresidue was partitioned between EtOAc and water. The aqueous layer wasextracted twice with EtOAc. A 2 M NaOH solution was added to the aqueouslayer until pH reached 8-9 and further extraction with EtOAc wasperformed. The combined organic layers were then washed with brine,dried over Na₂SO₄, filtered and concentrated in vacuo. The solid wastriturated with heptane (100 mL) at r.t. overnight, filtered off, washedwith heptane and Et₂O, and dried to afford the expected compound.

¹H NMR δ (ppm) (400 MHz, CDCl₃): 8.17 (2H, dd), 7.18 (2H, app t), 6.99(2H, bs), 3.61 (3H, s), 3.09-2.98 (8H, m), 2.75 (2H, q), 2.61 (3H, s),1.34 (3H, t).

LC-MS: MW (calcd): 475; m/z MW. (obsd): 476 (M+1).

1.2.7.9. General Method F6

To a solution of the imidazo[1,2-a]pyridine-3-ylamine derivative (1 eq.)in a mixture THF/MeOH with AcOH (0 to 0.05 eq.) is added PtO₂ (15%) orPd/C (10%). The flask is evacuated and backfilled with argon. Then thereaction is evacuated and backfilled with H₂ and stirred at r.t. underatmospheric pressure until completion. The crude product is filteredthrough a pad of Clarcel and washed with MeOH. The filtrate isconcentrated under reduced pressure. The residue is purified tochromatography on silica gel to afford the expected compound.

1.2.7.10. Illustrative synthesis of4-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-a]pyridin-6-yl)-piperidine-1-carboxylicacid tert-butyl ester

4-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-a]pyridin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester was prepared from Intermediate Gen-5-b andtert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate using method F2.

To a solution of4-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-a]pyridin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (60.0 g, 97 mmol, 1 eq.) in a mixture of THF (750mL) and MeOH (750 mL) with AcOH (0.279 mL, 4.83 mmol, 0.05 eq.) wasadded Pd/C (10.3 g, 9.67 mmol, 0.1 eq.). The flask was evacuated andbackfilled with argon. Then the reaction was evacuated and backfilledwith H₂ and stirred at r.t. under atmospheric pressure overnight. Thecrude product was filtered through a pad of Clarcel and washed withMeOH. The filtrate was concentrated under reduced pressure. The residuewas purified to chromatography on silica gel to afford the expectedcompound.

LC-MS: MW (calcd): 535; m/z MW. (obsd): 536 (M+1).

1.2.7.11. General Method F7

To a solution of the amino derivative in DCM are added TEA (5 eq.) thenBoc₂O (0.9 eq.). The reaction mixture is stirred at r.t. for 1.5 h thendiluted with DCM. The organic layer is separated and the aqueous layerextracted with DCM. The combined organic layers are washed with waterand brine, dried over Na₂SO₄, filtered and concentrated in vacuo toafford the corresponding intermediate.

1.2.7.12. Illustrative synthesis of4-(2-Ethyl-3-methylamino-imidazo[1,2-a]pyridin-6-yl)-piperidine-1-carboxylicacid tert-butyl ester

(2-Ethyl-6-piperidin-4-yl-imidazo[1,2-a]pyridin-3-yl)-methyl-amine isprepared from intermediate Gen-3-b through successive methods F2 (withtert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate), F6 and D1.

To a solution of(2-Ethyl-6-piperidin-4-yl-imidazo[1,2-a]pyridin-3-yl)-methyl-amine (1.67g, 4.15 mmol, 1 eq.) in DCM (35 mL) were added TEA (2.9 mL, 20.7 mmol, 5eq.) then Boc₂O (815 mg, 3.74 mmol, 0.9 eq.). The reaction mixture wasstirred at r.t. for 1.5 h then diluted with DCM. The organic layer wasseparated and the aqueous layer extracted with DCM. The combined organiclayers were washed with water and brine, dried over Na₂SO₄, filtered andconcentrated in vacuo to afford the expected compound.

LC-MS: MW (calcd): 358; m/z MW. (obsd): 359 (M+1).

1.2.7.13. General Method F8

To a solution of amino derivative (1 eq.) in MeCN are added potassiumcarbonate (2 eq.) or TEA (5 eq.) and halogenated derivative Gen-13 (orcommercially available products) (1.5 eq.). The reaction mixture isheated between 70° C. and reflux for 1.5 h to 6 h then cooled to r.t.The reaction mixture is quenched with water and diluted with EtOAc. Theaqueous layer is extracted with EtOAc. The combined organic layers arewashed with water and brine, dried over Na₂SO₄ and concentrated invacuo. The residue is purified by chromatography on silica gel todeliver the expected compound. If the product is precipitated in thereaction mixture the following work up is used: after cooling to r.t.,the reaction mixture is filtered. The solid is washed with MeCN, waterand dried in vacuo to afford the expected product.

1.2.7.14. Illustrative synthesis of Compound 2:2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

To a solution of amine compound 1 (12.6 g, 27 mmol, 1 eq.) in 100 mL ofMeCN were added potassium carbonate (7.3 g, 53 mmol, 2 eq.) and Gen13-a(5.2 g, 34 mmol, 1.3 eq.). The reaction mixture was refluxed for 5.5 hthen cooled to r.t. and stirred for 40 h. The crude product was filteredand washed with MeCN. The collected precipitate was then suspended in300 mL of water, stirred for 1 h, filtered, and finally washed withwater and MeCN. The solid obtained was dried in vacuo for 48 h to affordCompound 2.

¹H NMR (400 MHz, CDCl₃) δ ppm 8.20-8.12 (2H, m), 7.22-7.13 (2H, m), 6.99(2H, s), 4.68 (1H, m), 4.43 (1H, dd), 4.26 (1H, dd), 4.14-4.05 (1H, m),3.88 (1H, dd), 3.61 (3H, s), 3.58-3.52 (1H, m), 3.14-3.02 (6H, m), 2.74(2H, q), 2.70-2.62 (4H, m), 2.59 (3H, s), 1.33 (3H, t)

LC-MS: MW (calcd): 588; m/z MW. (obsd): 589 (M+1).

1.2.7.15. General Methods F9 1.2.7.15.1. General Method F9a

To a solution of acid (1.1 eq.) in DCM are added HOBT (1.2 eq.) andEDC.HCl (1.2 eq.). The reaction mixture is stirred at r.t. for 45 minthen prepared solution of amine (1 eq.) in DCM with TEA (3 eq.) isadded. The reaction mixture is stirred at r.t. until completion, thenwater and a solution of HCl 1 M are added, the aqueous layer isextracted with DCM, the organic layer is washed with a saturated Na₂CO₃solution, and brine, dried over Na₂SO₄, filtered and concentrated invacuo. The residue is purified by chromatography on silica gel to affordthe expected compound.

1.2.7.15.2. Illustrative synthesis of Compound 205:1-Benzyl-4-[4-(2-ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-a]pyridin-6-yl)-piperazine-1-carbonyl]-pyrrolidin-2-one

To a solution of 1-benzyl-5-oxo-pyrrolidine-3-carboxylic acid (38 mg,0.173 mmol, 1.1 eq.) in DCM (3 mL) were added HOBT (25 mg, 0.188 mmol,1.2 eq.) and EDC.HCl (36 mg, 0.188 mmol, 1.2 eq.). The reaction mixturewas stirred at r.t. for 45 min then Gen-10-e (80 mg, 0.157 mmol, 1 eq.)dissolved in DCM (1 mL) with TEA (65 μL, 0.471 mmol, 3 eq.) was added.The reaction mixture was stirred at r.t overnight, then water and asolution of HCl 1 M were added, the aqueous layer was extracted withDCM, the organic layer was washed with a saturated Na₂CO₃ solution, andbrine, dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by chromatography on silica gel to afford theCompound 205

LC-MS: MW (calcd): 637; m/z MW. (obsd): 638 (M+1).

1.2.7.15.3. General Method F9b

To a solution of amine (1 eq.) in DCM are added TEA (4 to 5 eq.)followed by acyl chloride derivative (1.2 to 2 eq.). The reactionmixture is stirred at r.t. until completion, then is quenched with waterand the aqueous layer is extracted with DCM twice. The organic layer iswashed with water, and brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue is purified by chromatography onsilica gel to afford the expected compound.

1.2.7.15.4. Illustrative synthesis of Compound 48:1-{3-[4-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-a]pyridin-6-yl)-piperazine-1-carbonyl]-pyrrolidin-1-yl}-ethanone

To a solution of compound 47 (30 mg, 0.049 mmol, 1 eq.) in DCM (2 mL)were added TEA (34 μL, 0.247 mmol, 5 eq.) followed by the acetylchloride (7 μL, 0.099 mmol, 2 eq.). The reaction mixture was stirred atr.t. for 2 h, then quenched with water and the aqueous layer wasextracted with DCM twice. The organic layer was washed with water, andbrine, dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by chromatography on silica gel to afford Compound48

LC-MS: MW (calcd): 575; m/z MW. (obsd): 576 (M+1).

1.2.7.16. General Method F10

To a solution of the appropriate amine (1.0 eq.) in MeOH are added TEA(0 to 3 eq.), acetic acid if needed (0 to 3 eq.) and the aldehyde orketone (1.5 to 2 eq.). The reaction mixture is stirred at r.t. for 10min then NaBH₃CN (1.5 to 3 eq.) is added. The reaction mixture isstirred at r.t. overnight, then concentrated in vacuo. The residue isdissolved in a mixture of DCM and water, the two phases are separatedand the aqueous phase is extracted with DCM. The combined organic layersare washed with a saturated Na₂CO₃ solution, and brine, dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel to afford the expected compound.

1.2.7.17. Illustrative synthesis of Compound 217:[6-(1-Benzyl-piperidin-4-yl)-2-ethyl-imidazo[1,2-a]pyridin-3-yl]-[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amine

To a solution of amine Gen-10-c (40 mg, 0.085 mmol, 1.0 eq.) in MeOH (2mL) were added TEA (35 μL, 0.254 mmol, 3 eq.) and the benzaldehyde (17μL, 0.169 mmol, 2 eq.). The reaction mixture was stirred at r.t. for 10min then NaBH₃CN (158 mg, 0.254 mmol, 3 eq.) was added. The reactionmixture was stirred at r.t. overnight, then concentrated in vacuo. Theresidue was dissolved in a mixture of DCM and water, the two phases wereseparated and the aqueous phase is extracted with DCM. The combinedorganic layers were washed with a saturated Na₂CO₃ solution, and brine,dried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by chromatography on silica gel to afford Compound 217.

LC-MS: MW (calcd): 525; m/z MW. (obsd): 526 (M+1).

1.2.7.18. General Method F11

To a solution of the appropriate amine (1 eq.) in DCM at 0° C. are addedTEA (3 eq.) and sulfonyl chloride (1.3 to 2 eq.). The reaction mixtureis stirred at r.t. until completion. The crude product is quenched withwater and diluted with DCM, the aqueous layer is extracted with DCM. Thecombined organic layers are washed with water and brine, dried overNa₂SO₄, filtered and concentrated in vacuo. The residue is purified bychromatography on silica gel to afford the expected compound.

1.2.7.19. Illustrative synthesis of Compound 80:N-(2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine

To a solution of the previously prepared amine Gen-10-c (2.9 g, 6.7mmol, 1 eq.) in DCM at 0° C. were added TEA (2.8 mL, 20.1 mmol, 3 eq.)and mesyl chloride (1.03 mL, 13.3 mmol, 2 eq.). The reaction mixture wasstirred at r.t. for 3 h. The crude product was quenched with water anddiluted with DCM, the aqueous layer was extracted with DCM. The combinedorganic layers were washed with water and brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel (elution DCM/MeOH 90/10) to afford Compound80.

LC-MS: MW (calcd): 513; m/z MW. (obsd): 514 (M+1).

1.2.7.20. General Methods F12 1.2.7.20.1. General Methods F12a

To a solution of the corresponding nucleophile (2 to 6 eq.) in THF orDMF are added NaI or KI (cat) and halogenoalkyl group containingimidazo[1,2-a]pyridine-3-ylamine derivative Gen-10 (1 eq.). When thenucleophile amine corresponding as a hydrochloride, the amine ispremixed with K₂CO₃ (5 to 6 eq.) in the solvent for 10 min before theaddition of the catalyst and the halogenoalkyl group containingimidazo[1,2-a]pyridine-3-ylamine derivative. The reaction mixture isheated between 80° C. and 150° C. under microwave irradiation or inthermic conditions for 1.5 to 3 h. After cooling, water and EtOAc areadded to the reaction mixture, the aqueous layer is extracted with EtOActwice. The combined organic layers are washed with water and brine,dried over Na₂SO₄, filtered and concentrated in vacuo. The residue ispurified by chromatography on silica gel to afford the expectedcompound.

1.2.7.20.2. Illustrative synthesis of Compound 89:{2-Ethyl-6-[1-(3-pyrrolidin-1-yl-propane-1-sulfonyl)-piperidin-4-yl]-imidazo[1,2-a]pyridin-3-yl}-[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amine

To a solution of the pyrrolidine (36 μL, 0.434 mmol, 5 eq.) in THF (3mL) were added NaI (2 mg, cat) and Compound 86 (50 mg, 0.087 mmol, 1eq.). The reaction mixture was heated at 150° C. under microwaveirradiation for 2 h. After cooling, water and EtOAc were added to thereaction mixture, the aqueous layer was extracted with EtOAc twice. Thecombined organic layers were washed with water and brine, dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel to afford Compound 89.

LC-MS: MW (calcd): 610; m/z MW. (obsd): 611 (M+1).

1.2.7.20.3. Illustrative synthesis of Compound 131:{2-(3,3-Difluoro-azetidin-1-yl)-1-[4-(2-ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-a]pyridin-6-yl)-piperidin-1-yl]-ethanone

To a solution of the 3,3-difluoroazetidine hydrochloride (40 mg, 0.31mmol, 2 eq.) in DMF (1.5 mL) was added K₂CO₃ (111 mg, 0.80 mmol, 5 eq.),the reaction mixture was stirred at r.t. for 10 min., then KI (4 mg,cat) and the2-Chloro-1-[4-(2-ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-a]pyridin-6-yl)-piperidin-1-yl]-ethanone(1 eq.) were added. The reaction mixture is heated at 80° C. in thermicconditions for 2 h. After cooling, water and EtOAc were added to thereaction mixture, the aqueous layer was extracted with EtOAc twice. Thecombined organic layers were washed with water and brine, dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel to afford Compound 131.

LC-MS: MW (calcd): 568; m/z MW. (obsd): 569 (M+1).

1.2.7.20.4. General Methods F12b

To a solution of the halogenoalkyl group containingimidazo[1,2-a]pyridine-3-ylamine derivative (1 eq.) in DMF is addedpotassium acetate (3 eq.), the reaction mixture is heated at 90° C. for4 h to overnight. After cooling, water and EtOAc are added to thereaction mixture, the aqueous layer is extracted with EtOAc twice. Thecombined organic layers are washed with water and brine, dried overNa₂SO₄, filtered and concentrated in vacuo. The residue is purified bychromatography on silica gel to afford the expected compound.

1.2.7.20.5. Illustrative synthesis of Compound 74: Acetic acid3-[4-(2-ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-a]pyridin-6-yl)-3,6-dihydro-2H-pyridine-1-sulfonyl]-propyl ester

To a solution of the{6-[1-(3-Chloro-propane-1-sulfonyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-2-ethyl-imidazo[1,2-a]pyridin-3-yl}-[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amine(105 mg, 0.183 mmol, 1 eq.) in DMF (3 mL) was added potassium acetate(54 mg, 0.549 mmol, 3 eq.), the reaction mixture was heated at 90° C.for 4 h. After cooling, water and EtOAc were added to the reactionmixture, the aqueous layer was extracted with EtOAc twice. The combinedorganic layers were washed with water and brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel to afford Compound 74.

LC-MS: MW (calcd): 597; m/z MW. (obsd): 598 (M+1).

1.2.7.21. General Method F13

To a solution of the corresponding ester (1 eq.) in EtOH or a mixture ofTHF/water is added an excess of a solution of NaOH 1 N or LiOH (5 eq.).The reaction mixture is stirred at r.t. overnight, then concentrated invacuo and the residue is dissolved in a mixture of DCM and water. Theaqueous layer is extracted with DCM twice, the combined organic layersare washed with a saturated NaHCO₃ solution, and brine, dried overNa₂SO₄, filtered and concentrated in vacuo. The residue is purified bychromatography on silica gel to afford the expected compound.

1.2.7.22. Illustrative synthesis of Compound 94:3-[4-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-a]pyridin-6-yl)-piperidine-1-sulfonyl]-propan-1-ol

To a solution of the compound 93 (1.14 g, 1.901 mmol, 1 eq.) in EtOH (15mL) was added an excess of a solution of NaOH 1 N (10 mL). The reactionmixture was stirred at r.t. overnight, then concentrated in vacuo andthe residue was dissolved in a mixture of DCM and water. The aqueouslayer was extracted with DCM twice, the combined organic layers werewashed with a saturated NaHCO₃ solution, and brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel to afford Compound 94.

LC-MS: MW (calcd): 557; m/z MW. (obsd): 558 (M+1).

1.2.7.23. General Method F14

To a solution of thiazole derivative (1 eq.) in THF are addedformaldehyde (48 eq.), TEA (5.9 eq.) and water. The reaction mixture isheated to 140° C. under microwave irradiation for 2.5 h. The crudeproduct mixture is quenched with water and a NH₃ aqueous solution. Theaqueous layer is extracted with EtOAc. The combined organic layers arewashed with water and brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue is purified by chromatography onsilica gel to deliver the expected compound.

1.2.7.24. Illustrative synthesis of compound 147:(2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazol-5-yl)methanol

To a solution of compound 80 (500 mg, 0.97 mmol, 1 eq.) in THF (3.5 mL)were added formaldehyde (37% in water, 3.5 mL, 47 mmol, 48 eq.), TEA(800 μL, 5.75 mmol, 5.9 eq.) and water (3.5 mL). The reaction mixturewas heated to 140° C. under microwave irradiation for 2.5 h. The crudemixture was quenched with water and a NH₃ aqueous solution. The aqueouslayer was extracted with EtOAc. The combined organic layers were washedwith water and brine, dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by chromatography on silica gel (elutionwith DCM/MeOH: 100/0 to 97/3) to afford Compound 147.

LC-MS: MW (calcd): 543; m/z MW. (obsd): 544 (M+1).

1.2.7.25. General Method F15

To a solution of thiazole derivative (1 eq.) in pyridine at 0° C. isslowly added trifluoroacetic anhydride (6 eq.). The reaction mixture isstirred at 0° C. for 1 h then partitioned between DCM and water. Theorganic phase is separated. The aqueous layer is extracted with DCM. Thecombined organic layers are washed with water and brine, dried overMgSO₄, filtered and concentrated in vacuo. The residue is purified bychromatography on silica gel to afford the expected compound.

1.2.7.26. Illustrative synthesis of compound 160:1-(2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazol-5-yl)-2,2,2-trifluoroethanone

To a solution of compound 80 (80 mg, 0.16 mmol, 1 eq.) in pyridine (5mL) at 0° C. was slowly added trifluoroacetic anhydride (150 μL, 0.93mmol, 6 eq.). The reaction mixture was stirred at 0° C. for 1 h thenpartitioned between DCM and water. The organic phase was separated. Theaqueous layer was extracted with DCM. The combined organic layers werewashed with water and brine, dried over MgSO₄, filtered and concentratedin vacuo. The residue was purified by chromatography on silica gel(elution with DCM/MeOH: 100/0 to 95/5) to afford Compound 160.

LC-MS: MW (calcd): 609; m/z MW. (obsd): 610 (M+1).

1.2.7.27. General Methods F16

1.2.7.27.1. General Method F16a

To a solution of thiazole derivative (1 eq.) in DCM is addedpolymer-supported bromide (1.1 eq.). The mixture is stirred vigorouslyat r.t. for 4 h. The crude mixture is filtered, the residue is washedwith DCM and MeOH. The filtrate is concentrated in vacuo, then dilutedwith DCM, washed with a saturated NaHCO₃ solution, water and brine,dried over Na₂SO₄ and concentrated in vacuo to afford the expectedcompound.

1.2.7.27.2. Illustrative synthesis of2-[4-(3-{[5-Bromo-4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-2-ethyl-imidazo[1,2-a]pyridin-6-yl)-piperazin-1-yl]-1-(3-hydroxymethyl-cyclobutyl)-ethanone

To a solution of compound 34 (200 mg, 0.36 mmol, 1 eq.) in DCM (7.5 mL),was added polymer-supported bromide (1.2-1.8 mmol/g, 244 mg, 0.39 mmol,1.1 eq.). The mixture was stirred vigorously at r.t. for 4 h. The crudemixture was filtered; the residue was washed with DCM and MeOH. Thefiltrate was concentrated in vacuo, then diluted with DCM, washed with asaturated NaHCO₃ solution, water and brine, dried over Na₂SO₄ andconcentrated in vacuo to afford the expected compound.

LC-MS: MW (calcd): 641 (⁷⁹Br), 643 (⁸¹Br); m/z MW. (obsd): 642 (⁷⁹BrM+1), 644 (⁸¹Br M+1).

1.2.7.27.3. General Method F16b

To a solution of thiazole derivative (1 eq.) in MeCN is addedselectfluor (1.2 eq.) portionwise. The mixture is stirred at r.t. for 20h to 2 days. The crude mixture is concentrated in vacuo, the residue isdissolved in mixture of EtOAc and water. The aqueous layer is extractedwith EtOAc twice, the combined organic layers are washed with water,then brine, dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue is purified by chromatography on silica gel to afford theexpected compound.

1.2.7.27.4. Illustrative synthesis of compound 95:3-[4-(2-Ethyl-3-{[5-fluoro-4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-a]pyridin-6-yl)-piperidine-1-sulfonyl]-propan-1-ol

To a solution of compound 94 (90 mg, 0.161 mmol, 1 eq.) in MeCN (5 mL)was added selectfluor (69 mg, 0.194 mmol, 1.2 eq.) portionwise. Themixture was stirred at r.t. for 2 days. The crude mixture isconcentrated in vacuo, the residue was dissolved in mixture of EtOAc andwater. The aqueous layer was extracted with EtOAc twice, the combinedorganic layers were washed with water, and brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel to afford Compound 95.

LC-MS: MW (calcd): 575; m/z MW. (obsd): 576 (M+1).

1.2.7.28. General Method F17

To a solution of the above prepared bromide (1 eq.) in pyridine is addedcopper cyanide (5 eq.). The mixture is heated to 160° C. under microwaveirradiation for 2 h. The crude mixture is quenched with water and a NH₃aqueous solution, and diluted in EtOAc. The organic layer is separated,the aqueous layer is extracted with EtOAc. The combined organic layersare washed with water and brine, dried over Na₂SO₄ and concentrated invacuo. The residue is purified by chromatography on silica gel orpreparative LC-MS to afford the expected compound.

1.2.7.29. Illustrative synthesis of compound 139:2-((2-ethyl-6-(4-(2-(3-(hydroxymethyl)azetidin-1-yl)-2-oxoethyl)piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

The bromo derivative (128 mg, 0.20 mmol, 1 eq.), obtained by brominationof compound 34 by the general method F16a, was dissolved in pyridine (3mL), then copper cyanide (89 mg, 1 mmol, 5 eq.) was added. The mixturewas heated to 160° C. under microwave irradiation for 2 h. The crudemixture was quenched with water and a NH₃ aqueous solution, and dilutedin EtOAc. The organic layer was separated; the aqueous layer wasextracted with EtOAc. The combined organic layers were washed with waterand brine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by preparative LC-MS to afford Compound 139.

LC-MS: MW (calcd): 588; m/z MW. (obsd): 589 (M+1).

1.2.7.30. General Method F18

To a solution of ester derivative (1 eq.) in anhydrous THF at 0° C. isadded LiBH₄ (2 M in THF, 5 eq.). The reaction mixture is allowed to warmto r.t. then stirred overnight at 80° C. Solid sodium sulfate hydrate isadded and the mixture is kept stirring for 10 min. The reaction mixtureis then filtered and the solid is rinsed with THF. The filtrate isconcentrated to give the hydroxymethyl derivative that can be used assuch in the next step or purified by chromatography.

1.2.7.31. Illustrative synthesis of4-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-5-hydroxymethyl-thiazol-2-yl]-methyl-amino}-imidazo[1,2-a]pyridin-6-yl)-piperazine-1-carboxylicacid tert-butyl ester

To a solution of Intermediate Gen-10-ag (723 mg, 1.22 mmol, 1 eq.) inanhydrous THF (12 mL) at 0° C. was added LiBH₄ (2 M in THF, 3 mL, 6.1mmol, 5 eq.). The reaction mixture was allowed to warm to r.t. thenstirred overnight at 80° C. Solid sodium sulfate hydrate was added andthe mixture was kept stirring for 10 min. The reaction mixture was thenfiltered and the solid rinsed with THF. The filtrate was concentrated togive the expected compound used as such in the next step.

LC-MS: MW (calcd): 566; m/z. (obsd): 567 (M+1).

1.2.7.32. General Method F19: General Synthesis of Oxazoline Derivative

3-Amino-imidazo[1,2-a]pyridine-6-carboxylic acid (2-hydroxy-ethyl)-amidederivative is prepared from Intermediate Gen-5 (with R^(y)═CO₂R) and2-ethanolamine derivative via successive general synthetic methods F13and F9a. To the 3-amino-imidazo[1,2-a]pyridine-6-carboxylic acid(2-hydroxy-ethyl)-amidederivative prepared from Intermediate Gen-5-aawith the desired amine via successive general synthetic methods F13 andF9a (1 eq.) in anhydrous DCM are added triphenylphosphine (1.5 eq.) andDDQ (1.5 eq.). The reaction mixture is stirred at r.t. for 0.5 h thenthe solvent is evaporated. The crude product is purified bychromatography to give the expected compound.

1.2.7.33. Illustrative synthesis of compound 240: [6-(4,5-Dihydro-oxazol-2-yl)-2-ethyl-imidazo[1,2-a]pyridin-3-yl]-[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amine

To a solution of3-((4-(4-chlorophenyl)thiazol-2-yl)(methyl)amino)-2-ethyl-N-(2-hydroxyethyl)imidazo[1,2-a]pyridine-6-carboxamide(40 mg, 0.09 mmol, 1 eq.), prepared from Intermediate Gen-5-aa andethanolamine via successive general synthetic methods F13 and F9a) inDCM (1.5 mL), were added triphenylphosphine (35 mg, 0.13 mmol, 1.5 eq.)and DDQ (30 mg, 0.13 mmol, 1.5 eq.). The reaction mixture was stirred atroom temperature for 0.5 h and then concentrated. The crude product waspurified by chromatography on silica gel (eluent DCM/MeOH 100/0 to 97/3)to give Compound 240.

LC-MS: MW (calcd): 437; m/z. (obsd): 438 (M+1).

1.2.7.34. General Method E1

Intermediates Gen-10 are prepared from intermediates Gen-9 according togeneral method E1 described previously.

1.2.7.35. General Method E4

To a previously degassed solution of halogeno heteroaryl derivative (1eq.), the imidazo[1,2-a]pyridine-3-ylamine derivative (1.2 eq.), cesiumcarbonate (3 eq.), and Xantphos (0.15 eq.) in dioxane under argon isadded Pd(OAc)₂ (0.2 eq.). The reaction mixture is heated to reflux untilcompletion. After cooling to r.t., the reaction mixture is partitionedbetween water and EtOAc and the layers separated. The aqueous layer isextracted with EtOAc. The combined organic layers are washed with waterand brine, dried Na₂SO₄, filtered and concentrated in vacuo. The crudeproduct is purified by chromatography on silica gel to afford theexpected intermediate.

1.2.7.36. Illustrative synthesis of4-(2-Ethyl-3-{[3-(4-fluoro-phenyl)-[1, 2,4]thiadiazol-5-yl]-methyl-amino}-imidazo[1,2-a]pyridin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

To a previously degassed solution of5-chloro-3-(4-fluorophenyl)-1,2,4-thiadiazole (800 mg, 3.73 mmol, 1eq.), amine Gen-9-c (1.57 g, 4.41 mmol, 1.2 eq.), cesium carbonate (3.64g, 11.2 mmol, 3 eq.), and Xantphos (323 mg, 0.56 mmol, 0.15 eq.) indioxane (20 mL) under argon was added Pd(OAc)₂ (167 mg, 0.74 mmol, 0.2eq.). The reaction mixture was heated to reflux for 3 h. After coolingto r.t., the reaction mixture was partitioned between water and EtOAcand the layers separated. The aqueous layer was extracted twice withEtOAc. The combined organic layers were washed with water and brine,dried Na₂SO₄, filtered and concentrated in vacuo. The crude product waspurified by chromatography on silica gel (elution with heptane/EtOAc:80/20 to 40/60) to afford the expected compound.

LC-MS: MW (calcd): 534; m/z MW. (obsd): 535 (M+1).

1.2.7.37. General Method E5

Step i

A solution of imidazo[1,2-a]pyridine-3-ylamine derivative (1 eq.) and3-Bromo-5-chloro-1,2,4-thiadiazole (3.3 eq.) in MeCN (2.5 mL) underargon in a sealed tube is heated at 90° C. overnight. After cooling tor.t. the mixture is concentrated in vacuo. The residue is purified bychromatography on silica gel.

Step ii

To a solution of the above prepared bromo derivative (1 eq.) in amixture dioxane/water under argon are added cesium fluoride (2.1 eq.),the corresponding aryl boronic acid derivative (1.2 eq.), and thenPdCl₂(P-tBu₂(p-NMe₂Ph))₂ (0.1 eq.). The reaction mixture is heated at80° C. for 48 h. After cooling to r.t., the reaction mixture ispartitioned between water and EtOAc and the layers separated. Theaqueous layer is extracted twice with EtOAc. The combined organic layersare washed with water and brine, dried Na₂SO₄, filtered and concentratedin vacuo. The crude product is purified by chromatography on silica gelto afford the expected intermediate.

1.2.7.38. Illustrative synthesis of4-(3-{[3-(2-Cyano-4-fluoro-phenyl)-[1, 2,4]thiadiazol-5-yl]-methyl-amino}-2-ethyl-imidazo[1,2-a]pyridin-6-yl)-piperidine-1-carboxylicacid tert-butyl ester

Step i

A solution of Intermediate Gen-9-d (500 mg, 1.40 mmol, 1 eq.) and3-Bromo-5-chloro-1,2,4-thiadiazole (917 mg, 4.61 mmol, 3.3 eq.) in MeCN(2.5 mL) under argon in a sealed tube was heated at 90° C. overnight.After cooling to r.t. the mixture was concentrated in vacuo. The residuewas purified by chromatography on silica gel (elution with DCM/MeOH:100/0 to 96/4) to afford the expected compound.

LC-MS: MW (calcd): 520 (⁷⁹Br), 522 (⁸¹Br); m/z MW. (obsd): 521 (⁷⁹BrM+1), 523 (⁸¹Br M+1).

Step ii

To a solution of bromide obtained previously in step i) (120 mg, 0.23mmol, 1 eq.) in a mixture dioxane/water (1.1/0.68 mL) under argon wereadded cesium fluoride (73 mg, 0.48 mmol, 2.1 eq.),2-Cyano-4-fluorobenzeneboronic acid, pinacol ester (69 mg, 0.28 mmol,1.2 eq.), and then Pd(P-tBu₂(p-NMe₂Ph))₂ (16 mg, 0.022 mmol, 0.1 eq.).The reaction mixture was heated at 80° C. for 48 h.

After cooling to r.t., the reaction mixture was partitioned betweenwater and EtOAc and the layers separated. The aqueous layer wasextracted twice with EtOAc. The combined organic layers were washed withwater and brine, dried over Na₂SO₄, filtered and concentrated in vacuo.The crude product was purified by chromatography on silica gel (elutionwith DCM/MeOH: 100/0 to 96/4) to afford the expected compound.

LC-MS: MW (calcd): 561; m/z MW. (obsd): 562 (M+1).

1.2.8. General Method D1: Synthesis of Intermediate Gen-6

Intermediates Gen-6 are prepared from intermediates Gen-2 according togeneral method D1 described previously.

1.2.9. General Methods E1 or H1: Synthesis of Intermediate Gen-7

1.2.9.1. General Method E1

Intermediates Gen-7 are prepared from intermediates Gen-6 according togeneral method E1 described previously

1.2.9.2. General Method H1

Step i

To a solution of the corresponding intermediate (1 eq.) in DCM at 0° C.are added calcium carbonate (3 eq.) and a few min later thiophosgene(1.2 eq.). The reaction mixture is stirred at 0° C. for 3.5 h thenquenched with water. The layers are separated. The aqueous phase isextracted with DCM. The combined organic layers are washed with waterand brine, dried over Na₂SO₄ and concentrated in vacuo to give theexpected isothiocyanate.

Step ii

To a solution of the above prepared isothiocyanate (1 eq.) in DMF areadded DIPEA (1.1 eq.) and then the corresponding benzamidinehydrochloride (1 eq.). The reaction mixture is stirred at r.t.overnight. DIAD (1.1 eq.) is added and the resulting mixture is heatedat 80° C. for 45 min. Stirring is continued at r.t. for 3 h then waterand EtOAc were added. The layers are separated. The aqueous phase isextracted with EtOAc. The combined organic layers are washed with waterand brine, dried over Na₂SO₄ and concentrated in vacuo. The residue ispurified by chromatography on silica gel. and give Intermediate Gen-7

1.2.9.3. Illustrative synthesis of Intermediate Gen-7-a:(6-Bromo-2-ethyl-imidazo[1,2-a]pyridin-3-yl)-[3-(4-chloro-phenyl)-[1, 2,4]thiadiazol-5-yl]-amine

Step i

To a suspension of hydrochloride salt of Intermediate Gen-6-a (530 mg,1.92 mmol, 1 eq.) in DCM (7 mL) at 0° C. were added calcium carbonate(799 mg, 5.75 mmol, 3 eq.) and a few min later thiophosgene (176 μL,2.30 mmol, 1.2 eq.). The reaction mixture was stirred at 0° C. for 3.5 hthen quenched with water. The layers were separated. The aqueous phasewas extracted with DCM. The combined organic layers were washed withwater and brine, dried over Na₂SO₄ and concentrated in vacuo to afford6-Bromo-2-ethyl-3-isothiocyanato-imidazo[1,2-a]pyridine isothiocyanate.

LC-MS: MW (calcd): 281 (⁷⁹Br), 283 (⁸¹Br); m/z MW. (obsd): 282 (⁷⁹BrM+1), 284 (⁸¹Br M+1).

Step ii

To a solution of the above prepared isothiocyanate (305 mg, 1.08 mmol, 1eq.) in DMF (6 mL) were added DIPEA (207 μL, 1.19 mmol, 1.1 eq.) andthen 4-chloro-benzamidine hydrochloride (207 mg, 1.08 mmol, 1 eq.). Thereaction mixture was stirred at r.t. overnight. DIAD (236 μL, 1.19 mmol,1.1 eq.) was added and the resulting mixture was heated at 80° C. for 45min. Stirring was continued at r.t. for 3 h then water and EtOAc wereadded. The layers were separated. The aqueous phase was extracted withEtOAc. The combined organic layers were washed with water and brine,dried over Na₂SO₄ and concentrated in vacuo. The residue was purified bychromatography on silica gel (elution with heptane/EtOAc: 100/0 to 50/50then DCM/MeOH 98/2) to afford Intermediate Gen-7-a.

LC-MS: MW (calcd): 433 (⁷⁹Br), 435 (⁸¹Br); m/z MW. (obsd): 434 (⁷⁹Br),436 (⁸¹Br M+1).

1.2.10. General Methods F: Synthesis of Intermediate Gen-8

Intermediates Gen-8 are prepared from Intermediates Gen-3 according toone or several general methods F described previously

1.2.11. General Methods D and F: Synthesis of Intermediate Gen-9

1.2.11.1. General Method D and F

Intermediates Gen-9 are prepared from Intermediates Gen-8 according togeneral method D1 and one or several general methods F describedpreviously.

1.2.11.2. General Method F

Intermediates Gen-9 are prepared from Intermediate Gen-4 according toone or several general methods F described previously

1.2.12. General Method G1: General Synthesis of α-halogenoketones Gen-11

To a solution of ketone (1 eq.) in MeCN is added phenyltrimethylammoniumtribromide (1 eq.). The resulting mixture is stirred at r.t. for 3 h,and then is concentrated in vacuo. The organic residue is dissolved inEtOAc and the organic layer is washed with water, with brine, dried overNa₂SO₄, filtered and concentrated in vacuo to give the IntermediateGen-11. The crude product is used directly for the next step withoutpurification

1.2.13. Illustrative synthesis of Intermediate Gen-11-a:2-(2-Bromo-acetyl)-5-fluoro-benzonitrile

Step i

To a solution of 1-(2-Bromo-4-fluoro-phenyl)-ethanone (3.0 g, 13.82mmol, 1 eq.) in DMA (150 mL) under argon was added Zn(CN)₂ (1.6 g, 13.82mmol, 1 eq.), Pd₂(dba)₃ (1.26 g, 1.38 mmol, 0.1 eq.), dppf (1.53 g, 2.76mmol, 0.2 eq.) and Zn dust (107.8 mg, 1.65 mmol, 0.12 eq.). The reactionmixture was heated at 100° C. for 1.4 h, after cooling to r.t. themixture was slowly quenched by addition of water and then diluted withEtOAc. The organic layer was separated and the aqueous layer extractedwith EtOAc twice. The combined organic layers were washed with water,dried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified either by chromatography on silica gel to deliver Intermediate2-acetyl-5-fluoro-benzonitrile

LC-MS: MW (calcd): 163; m/z MW. (obsd): 164 (M+1).

Step ii

To a solution of 2-acetyl-5-fluoro-benzonitrile (1.52 g, 9.33 mmol, 1eq.) in MeCN (40 mL) was added phenyltrimethylammonium tribromide (3.51g, 1 eq.). The resulting mixture was stirred at r.t. for 3 h, and thenis concentrated in vacuo. The organic residue was dissolved in EtOAc andthe organic layer was washed with water, with brine, dried over Na₂SO₄,filtered and concentrated in vacuo to give the Intermediate Gen-11-a.The crude was used directly for the next step without purification

LC-MS: MW (calcd): 241 (⁷⁹Br), 243 (⁸¹Br); m/z MW. (obsd): 242 (⁷⁹BrM+1), 244 (⁸¹Br M+1).

1.2.14. General Method G2: General Synthesis of Chlorothiazoles Gen-12

Step i

To a solution of benzoylacetonitrile derivative (1 eq.) in EtOH is addedpyridine (1 eq.). The resulting mixture is stirred at 70° C. for 15 minthen cooled at r.t. A previously stirred suspension of thiourea (2 eq.)and iodine (1 eq.) in EtOH is then slowly added. After 1 h at r.t. acold 1 M Na₂S₂O₃ solution is added under stirring. The resultingprecipitate is filtered, washed with water, and finally dried undervacuo to afford the amino-4-phenyl-thiazole-5-carbonitrile derivative.

Step ii

To a solution of copper (II) chloride (1.2 eq.) in MeCN is addeddropwise tert-butyl nitrite (1.5 eq.). After stirring at r.t. for 30min, the amino-4-phenyl-thiazole-5-carbonitrile (1 eq.) is introducedportionwise and stirring is continued for 1 h. The reaction mixture isthen carefully quenched by addition of a 1 N HCl solution. After 15 minstirring, the organic phase is separated; the aqueous phase is furtherextracted with EtOAc. The combined organic layers are washed with brine,dried over Na₂SO₄, filtered and concentrated in vacuo. The crude productis filtered on a silica plug and eluted with DCM. Solvents areevaporated and the residue is finally triturated in heptane, filteredand dried to give Intermediate Gen-12.

1.2.15. Illustrative synthesis of Intermediate Gen-12-a2-Chloro-4-(4-fluoro-phenyl)-thiazole-5-carbonitrile

Step i

To a solution of 4-fluorobenzoylacetonitrile (50 g, 306 mmol, 1 eq.) inEtOH (600 mL) was added pyridine (24.7 mL, 306 mmol, 1 eq.). Theresulting mixture was stirred at 70° C. for 15 min then cooled to r.t. Apreviously stirred suspension of thiourea (46.7 g, 613 mmol, 2 eq.) andiodine (77.8 g, 306 mmol, 1 eq.) in EtOH (300 mL) was then slowly added.After 1 h at r.t. a cold 1 M Na₂S₂O₃ solution (360 mL) was added understirring. The resulting precipitate was filtered, washed with water, andfinally dried under vacuo to afford2-Amino-4-(4-fluoro-phenyl)-thiazole-5-carbonitrile.

¹H NMR δ (ppm) (400 MHz, DMSO): 8.26 (2H, s), 7.97 (2H, dd), 7.36 (2H,t)

Step ii

To a solution of copper (II) chloride (36.8 g, 273 mmol, 1.2 eq.) inMeCN (500 mL) was added dropwise tert-butyl nitrite (40.7 mL, 342 mmol,1.5 eq.). After stirring at r.t. for 30 min, amine previously obtainedin step i (50 g, 228 mmol, 1 eq.) was introduced portionwise andstirring was continued for 1 h. The reaction mixture was then carefullyquenched by addition of a 1 N HCl solution (750 mL). After 15 minstirring, the organic phase was separated; the aqueous phase was furtherextracted with EtOAc. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated in vacuo. The crudeproduct was filtered on a silica plug (250 g) and eluted with DCM.Solvents were evaporated and the residue was finally triturated inheptane, filtered and dried to afford2-Chloro-4-(4-fluoro-phenyl)-thiazole-5-carbonitrile (IntermediateGen-12-a).

¹H NMR δ (ppm) (400 MHz, DMSO): 8.06 (2H, dd), 7.46 (2H, dd)

1.2.16. General Method G3: General Synthesis of Intermediaire Gen-13

1.2.16.1. General Method G3a

To a suspension of potassium carbonate (2.2 eq.) in water is added theamine derivative (1 eq.). The reaction mixture is stirred at r.t. untilcomplete dissolution, then diluted with DCM and cooled to 0° C. prior tothe dropwise introduction of chloroacetyl chloride (1.2 eq.) over 30min. After 2 h stirring at r.t., the reaction mixture is filtered, theorganic layer and the aqueous phase are separated, and the aqueous phaseis extracted either with DCM or with a mixture of EtOAc/nBuOH 1:1. Thecombined organic layers are dried over Na₂SO₄, filtered and concentratedin vacuo. The residue is suspended in acetone and stirred vigorously for20 min, filtered and the filtrate was concentrated in vacuo to affordIntermediate Gen-13

1.2.16.2. Illustrative synthesis of Intermediate Gen-13-a:2-Chloro-1-(3-hydroxy-azetidin-1-yl)-ethanone

To a suspension of potassium carbonate (13.9 g, 100 mmol, 2.2 eq.) inwater (33.5 mL) was added hydroxyazetidine hydrochloride (5 g, 45.6mmol, 1 eq.). The reaction mixture was stirred at r.t. until completedissolution, then diluted with 33.5 mL of DCM and cooled to 0° C. priorto the dropwise introduction of chloroacetyl chloride (4.4 mL, 54.8mmol, 1.2 eq.) over 30 min After 2 h stirring at r.t., the reactionmixture was filtered, the organic layer was separated, and the aqueousphase was extracted with a mixture EtOAc/nBuOH 1:1 (6×16 mL). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was suspended in acetone (48 mL) andstirred vigorously for 20 min, filtered and the filtrate wasconcentrated in vacuo to afford Intermediate Gen-13-a.

¹H NMR δ (ppm) (400 MHz, CDCl₃): 4.77-4.68 (1H, m), 4.50 (1H, dd), 4.50(1H, dd), 4.32 (1H, dd), 4.16 (1H, dd), 3.89 (2H, s), 2.55 (1H, d).

1.2.17. General Method G3b

To a solution of chloroacetyl chloride (1 eq.) and TEA (1.5 eq.) in DCMat 0° C. is added the amine derivative (1.1 eq.). The reaction mixtureis stirred overnight at r.t., then concentrated in vacuo.

The residue is suspended in acetone and stirred vigorously for 20 min,filtered and the filtrate is concentrated in vacuo to affordIntermediate Gen-13 which is used directly without further purification.

1.2.17.1. Illustrative synthesis of Intermediate Gen-13-o:2-Chloro-N-methoxy-N-methylacetamide

To a solution of chloroacetyl chloride (0.195 mL, 1.21 mmol, 1 eq.) andTEA (0.253 mL, 1.81 mmol, 1.5 eq.) in 3 mL of DCM at 0° C. was added theN,O-dimethylhydroxylamine (0.081 g, 1.33 mmol, 1.1 eq.). The reactionmixture was stirred overnight at r.t., then concentrated in vacuo. Theresidue was suspended in acetone and stirred vigorously for 20 min,filtered and the filtrate was concentrated in vacuo to affordIntermediate Gen-13-o which was used directly without furtherpurification.

LC-MS: MW (calcd): 137 (³⁵Cl) 139 (³⁷Cl); m/z MW. (obsd): 138 (³⁵ClM+1), 140 (³⁷Cl M+1).

Example 2 Preparation of the Compounds of the Invention 2.1. Compound 1:2-((2-ethyl-8-methyl-6-(piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

Step i: 6-Bromo-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-3-ylamine

To a suspension of 2-amino-5-bromo-3-methylpyridine (420 g, 2.24 mol, 1eq.) previously washed before use with a saturated NaHCO₃ solution in1.5 L of toluene under nitrogen were added propionaldehyde (248 mL, 3.36mol, 1.5 eq.) and 1H-benzotriazole (281 g, 2.36 mol, 1.05 eq.). Theresulting mixture was stirred 4 h at r.t. before adding 3.5 L of EtOHand potassium cyanide (175 g, 2.70 mol, 1.2 eq.). The reaction mixturewas further stirred overnight at r.t. and 2 h at 78° C. After cooling tor.t., the mixture was quenched by addition of a 2.5 M NaOH solution (3L).

This experiment was performed in four batches with the same quantitiesof reagents, the crude mixture were then pooled together andconcentrated in vacuo to low volume. The remaining oil was diluted withEtOAc (15 L) and washed with a 2 M NaOH solution (2×2 L). The aqueouslayer was extracted twice with EtOAc (2×1 L). The combined organiclayers were then dried over Na₂SO₄, filtered and concentrated in vacuo.The crude mixture was dissolved in EtOH (2 L) and carefully added to asolution of acetyl chloride (1 L, 14.0 mol, 1.6 eq.) in EtOH (6 L). Theresulting reaction mixture was stirred at r.t. overnight and thenconcentrated to dryness. The residue was triturated in DCM (7 L) for 3days, the precipitate formed was collected, washed with DCM (2×500 mL)and dried to afford6-bromo-2-ethyl-8-methylimidazo[1,2-a]pyridin-3-amine as a hydrochloridesalt.

¹H NMR δ (ppm) (400 MHz, DMSO): 8.70 (1H, s), 7.75 (1H, s), 4.86 (3H,bs), 2.81 (2H, q), 2.56 (3H, s), 1.56 (3H, t).

LC-MS: MW (calcd): 253 (⁷⁹Br) and 255 (⁸¹Br); m/z. (obsd): 254 (⁷⁹BrM+1) and 256 (⁸¹Br M+1).

Step ii:N-(6-Bromo-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-3-yl)-formamide(Gen-2-d)

A suspension of the latter compound (785 g, 2.70 mol, 1 eq.) in formicacid (713 mL, 18.9 mol, 7 eq.) was heated to 80° C. for 2 h. The crudemixture was concentrated in vacuo to low volume (about 400 mL). Theresidue was brought up in water (1 L) and a 3 M solution of NaOH (2 L),and further basified with a saturated NaHCO₃ solution until foamingceased and pH reached 8-9. After homogenization for 1 h, the precipitatewas filtered and washed with water (2×300 mL). Purification was achievedby dissolution in a mixture of toluene and MeOH 3:1 (4 L) followed byconcentration in vacuo. Trituration of the residue in a mixture of 200mL of MeOH and 5 L of DIPE, decantation and filtration of the resultingsuspension afforded Intermediate Gen-2-dN-(6-bromo-2-ethyl-8-methylimidazo[1,2-a]pyridin-3-yl)formamide.

¹H NMR δ (ppm) (400 MHz, DMSO): presence of 2 rotamers 10.2 (1H, bs, onerotamer), 8.51 (1H, s, one rotamer), 8.36 (1H, s, one rotamer), 8.23(1H, s, one rotamer), 8.11 (1H, s, both rotamers), 7.23 (1H, s, onerotamer), 7.21 (1H, s, one rotamer), 2.63-2.60 (2H, m, both rotamers),2.58 (3H, s, one rotamer), 2.56 (3H, s, one rotamer), 1.24-1.17 (3H, m,both rotamers)

LC-MS: MW (calcd): 281 (⁷⁹Br) and 283 (⁸¹Br); m/z (obsd; m/z. (obsd):282 (⁷⁹Br M+1) and 284 (⁸¹Br M+1).

Step iii:N-(6-Bromo-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-3-yl)-N-methyl-formamide(Gen-3-e)

To a suspension of formamide Gen-2-d (720 g, 2.55 mol, 1 eq.) in 5 L ofacetone were added potassium carbonate (1 kg, 7.66 mol, 3 eq.) andmethyl iodide (700 g, 4.93 mol, 1.9 eq.). The reaction mixture washeated to 40° C. overnight. Additional methyl iodide (25 g, 0.18 mol,0.07 eq.) was then introduced and stirring continued for 1 h at 40° C.The reaction mixture was filtered and washed with acetone (2×300 mL) andDCM (2×300 mL). The filtrate was concentrated in vacuo and the residuewas partitioned between DCM (3 L) and water (1 L). The aqueous layer wasfurther extracted with DCM. The combined organic layers were then washedwith brine, dried over Na₂SO₄, filtered and concentrated in vacuo. Thesolid was triturated with Et₂O (1 L) at r.t. for 1 h, filtered off anddried to afford the Intermediate Gen-3-e.

¹H NMR δ (ppm) (400 MHz, CDCl₃), presence of 2 rotamers, major rotamer:8.19 (1H, s), 7.78 (1H, s), 7.15 (1H, s), 3.24 (3H, s), 2.72 (2H, q),2.59 (3H, s), 1.31 (3H, t)

¹H NMR δ (ppm) (400 MHz, CDCl₃), minor rotamer: 8.49 (1H, s), 7.65 (1H,s), 7.08 (1H, s), 3.36 (3H, s), 2.72 (2H, q), 2.59 (3H, s), 1.31 (3H, t)

LC-MS: MW (calcd): 295 (⁷⁹Br) and 297 (⁸¹Br); m/z. (obsd): 296 (⁷⁹BrM+1) and 298 (⁸¹Br M+1).

Step iv:(6-Bromo-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-3-yl)-methyl-amine

The above prepared formamide Gen-3-e (80 g, 270 mmol, 1 eq.) wasdissolved in a 1.25 M HCl solution in MeOH (540 mL, 2.5 eq.) and theresulting mixture was heated at 110° C. overnight. 270 mL of the 1.25 MHCl solution in MeOH were added and heating continued overnight. After48 h, additional 70 mL of the 1.25 M HCl solution in MeOH wereintroduced in the reaction mixture. Heating was maintained overnightuntil conversion was complete. The crude mixture was then concentratedin vacuo and the residue was partitioned between EtOAc (300 mL) andwater (700 mL). A saturated NaHCO₃ solution was added until pH reached8-9. The aqueous layer was extracted twice with EtOAc (2×300 mL). Thecombined organic layers were then washed with brine (200 mL), dried overNa₂SO₄, filtered and concentrated in vacuo to give(6-bromo-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-3-yl)-methyl-amineGen-4-d as a free base.

¹H NMR δ (ppm) (400 MHz, CDCl₃): 8.05 (1H, s), 7.04 (1H, s), 2.84-2.78(5H, m), 2.60 (3H, s), 1.35 (3H, t)

LC-MS: MW (calcd): 267 (⁷⁹Br) and 269 (⁸¹Br); m/z. (obsd): 268 (⁷⁹BrM+1) and 270 (⁸¹Br M+1).

Step v:2-[(6-Bromo-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-3-yl)-methyl-amino]-4-(4-fluoro-phenyl)-thiazole-5-carbonitrile

To a solution of amine Gen-4-d (4.4 g, 16.6 mmol, 1 eq.) in THF (44 mL)under argon was slowly added NaH (60% in oil suspension, 2.0 g, 50.0mmol, 3 eq.). The reaction mixture was heated at 90° C. for 30 min thencooled to 40° C. before adding the chlorothiazole Gen-12-a (4.74 g, 19.9mmol, 1.2 eq.). The reaction mixture was stirred at 90° C. overnight.After cooling to r.t. the mixture was slowly quenched by addition ofwater and then diluted with EtOAc. The organic layer was separated andthe aqueous layer extracted with EtOAc. The combined organic layers werethen washed with water and brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was triturated in Et₂O, filtered andwashed with Et₂O and MeCN. Recrystallization was performed in MeCN (180mL) to afford2-[(6-Bromo-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-3-yl)-methyl-amino]-4-(4-fluoro-phenyl)-thiazole-5-carbonitrile(Intermediate Gen-5-t).

¹H NMR δ (ppm) (400 MHz, CDCl₃): 8.15 (2H, dd), 7.80 (1H, s), 7.22-7.14(3H, m), 3.62 (3H, s), 2.77 (2H, q), 2.64 (3H, s), 1.35 (3H, t)

LC-MS: MW (calcd): 469 (⁷⁹Br), 471 (⁸¹Br); m/z. (obsd): 470 (⁷⁹Br M+1),472 (⁸¹Br M+1).

Step vi:4-(3-{[5-Cyano-4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-6-yl)-piperazine-1-carboxylicacid tert-butyl ester

To a solution of the above prepared bromide Gen-5-t (24.2 g, 51.5 mmol,1 eq.) in toluene (345 mL) under argon were successively added N-Bocpiperazine (14.4 g, 77.3 mmol, 1.5 eq.), sodium tert-butoxide (9.9 g,103 mmol, 2 eq.) and then JohnPhos (1.54 g, 5.15 mmol, 0.1 eq.) andPd₂(dba)₃ (2.36 g, 2.58 mmol, 0.05 eq.). The reaction mixture was heatedat 115° C. for 1 h. After cooling to r.t., the crude product wasfiltered on Celpure® P65 and the residue washed with water and EtOAc.The organic layer of the filtrate was washed with brine, dried overNa₂SO₄, filtered and concentrated in vacuo. The crude product waspurified by chromatography on silica gel (elution with heptane/EtOAc:90/10 to 20/80) to afford the expected compound.

¹H NMR δ (ppm) (400 MHz, CDCl₃): 8.16 (2H, dd), 7.17 (2H, app t), 6.99(2H, bs), 3.62-3.53 (4H, m) 3.60 (3H, s), 3.04-2.93 (4H, m), 2.74 (2H,q), 2.62 (3H, s), 1.47 (9H, s), 1.33 (3H, t)

LC-MS: MW (calcd): 575; m/z. (obsd): 576 (M+1).

Step vii:2-[(2-Ethyl-8-methyl-6-piperazin-1-yl-imidazo[1,2-a]pyridin-3-yl)-methyl-amino]-4-(4-fluoro-phenyl)-thiazole-5-carbonitrile

To a solution of4-(3-{[5-Cyano-4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-6-yl)-piperazine-1-carboxylicacid tert-butyl ester (24.4 g, 42 mmol, 1 eq.) in MeOH (100 mL) wasadded a 2 M HCl solution in Et₂O (127 mL, 254 mmol, 6 eq.). The reactionmixture was stirred at r.t. for 3.5 h then concentrated in vacuo. Theresidue was partitioned between EtOAc and water. The aqueous layer wasextracted twice with EtOAc. A 2 M NaOH solution was added to the aqueouslayer until pH reached 8-9 and further extraction with EtOAc wasperformed. The combined organic layers were then washed with brine,dried over Na₂SO₄, filtered and concentrated in vacuo. The solid wastriturated with heptane (100 mL) at r.t. overnight, filtered off, washedwith heptane and Et₂O, and dried to afford Compound 1.

¹H NMR δ (ppm) (400 MHz, CDCl₃): 8.17 (2H, dd), 7.18 (2H, app t), 6.99(2H, bs), 3.61 (3H, s), 3.09-2.98 (8H, m), 2.75 (2H, q), 2.61 (3H, s),1.34 (3H, t)

LC-MS: MW (calcd): 475; m/z. (obsd): 476 (M+1).

2.2. Compound 2:2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

To a solution of amine compound 1 (12.6 g, 27 mmol, 1 eq.) in 100 mL ofMeCN were added potassium carbonate (7.3 g, 53 mmol, 2 eq.) and Gen13-a(5.2 g, 34 mmol, 1.3 eq.). The reaction mixture was refluxed for 5.5 hthen cooled to r.t. and stirred for 40 h. The crude product was filteredand washed with MeCN. The collected precipitate was then suspended in300 mL of water, stirred for 1 h, filtered, and finally washed withwater and MeCN. The solid obtained was dried in vacuo for 48 h to affordCompound 2.

¹H NMR (400 MHz, CDCl₃) δ ppm 8.20-8.12 (2H, m), 7.22-7.13 (2H, m), 6.99(2H, s), 4.68 (1H, m), 4.43 (1H, dd), 4.26 (1H, dd), 4.14-4.05 (1H, m),3.88 (1H, dd), 3.61 (3H, s), 3.58-3.52 (1H, m), 3.14-3.02 (6H, m), 2.74(2H, q), 2.70-2.62 (4H, m), 2.59 (3H, s), 1.33 (3H, t)

LC-MS: MW (calcd): 588; m/z. (obsd): 589 (M+1).

2.3. Compounds 3-5

Compounds 3-5 listed in the table of compounds were prepared similarlyas compound 2 following general synthetic method F8 using Compound 1 andIntermediates Gen-13-b, Gen-13-g, Gen-13-h listed in the table ofsynthetic intermediates. Analytical details for these compounds and thefollowing compounds are provided in the table of analytical details.Analytical details for synthetic intermediates are provided in the tableof synthetic intermediates.

2.4. Compound 6:2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-3,3-dimethylpiperazin-1-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrileStep i: 2-{[6-(3,3-Dimethyl-piperazin-1-yl)-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-3-yl]-methyl-amino}-4-(4-fluoro-phenyl)-thiazole-5-carbonitrile

Intermediate Gen-10-x2-{[6-(3,3-Dimethyl-piperazin-1-yl)-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-3-yl]-methyl-amino}-4-(4-fluoro-phenyl)-thiazole-5-carbonitrileis prepared from Intermediate Gen-5-t and 2,2-dimethylpiperazinefollowing general synthetic method Fla.

Step ii: 2-[(2-Ethyl-6-{4-[2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]-3,3-dimethyl-piperazin-1-yl}-8-methyl-imidazo[1,2-a]pyridin-3-yl)-methyl-amino]-4-(4-fluoro-phenyl)-thiazole-5-carbonitrile

Compound 6 is obtained from Intermediate Gen-10-x by alkylation withIntermediate Gen-13-a following general synthetic method F8.

2.5. Compound 7:2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-8-methylimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone

Step i:(6-bromo-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-3-yl)-[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amine

Intermediate Gen-5-d(6-bromo-2-ethyl-8-methyl-imidazo[1,2-a]pyridin-3-yl)-[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amineis prepared from Intermediate Gen-4-d and 2-bromo-4′-fluoroacetophenonefollowing general synthetic method E1.

Step ii:(2-ethyl-8-methyl-6-piperazin-1-yl-imidazo[1,2-a]pyridin-3-yl)-[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amine

Intermediate Gen-10-n(2-ethyl-8-methyl-6-piperazin-1-yl-imidazo[1,2-a]pyridin-3-yl)-[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amineis prepared from Intermediate Gen-5-d and piperazine following generalsynthetic method Fla.

Step iii:2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-8-methylimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone

Compound 7 is obtained by alkylation of Intermediate Gen-10-n withIntermediate Gen-13-a following general synthetic method F8.

2.6. Compounds 8 and 9

Compounds 8-9 listed in the table of compounds are prepared similarly ascompound 7 following general synthetic method F8 using IntermediatesGen-10-n, Gen-13-g, Gen-13-h listed in the table of syntheticintermediates.

2.7. Compound 10:2-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

Step i)2-[(2-ethyl-8-methyl-6-piperidin-4-yl-imidazo[1,2-a]pyridin-3-yl)-methyl-amino]-4-(4-fluoro-phenyl)-thiazole-5-carbonitrile

Synthetic Intermediate Gen-10-o2-[(2-ethyl-8-methyl-6-piperidin-4-yl-imidazo[1,2-a]pyridin-3-yl)-methyl-amino]-4-(4-fluoro-phenyl)-thiazole-5-carbonitrileis obtained from Intermediate Gen-5-t using general synthetic methods F3followed by F5b.

Step ii)2-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

Compound 10 is then obtained by alkylation of Intermediate Gen-10-o withIntermediate Gen-13-a using general synthetic method F8.

2.8. Compound 11:2-(ethyl(2-ethyl-8-methyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

Step i)N-(6-bromo-2-ethyl-8-methylimidazo[1,2-a]pyridin-3-yl)-N-ethylformamide

Intermediate Gen-3-hN-(6-bromo-2-ethyl-8-methylimidazo[1,2-a]pyridin-3-yl)-N-ethylformamideis prepared from Intermediate Gen-2-d with iodoethane according togeneral synthetic method C2.

Step ii

Reaction of Intermediate Gen-3-h following general synthetic method D1affords Intermediate Gen-4-h.

Step iii

Reaction of Intermediate Gen-4-h with Intermediate Gen-12-a followinggeneral synthetic method E2 affords Intermediate Gen-5-h.

Step iv

Suzuki coupling of Intermediate Gen-5-h with1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridinefollowing general synthetic method F2 afford compound 11.

2.9. Compound 12:2-((2-ethyl-8-fluoro-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile

Step i

Intermediate Gen-1-a 2-amino-5-bromo-3-fluoropyridine is prepared from2-amino-3-fluoropyridine using general synthetic method A.

Step ii

Intermediate Gen-2-aN-(6-bromo-2-ethyl-8-fluoro-imidazo[1,2-a]pyridin-3-yl)-formamide isprepared from Intermediate Gen-1-a and propionaldehyde using generalsynthetic method B1.

Step ii

Intermediate Gen-2-a is methylated with iodomethane following generalmethod C2 to give Intermediate Gen-3-aN-(6-bromo-2-ethyl-8-fluoro-imidazo[1,2-a]pyridin-3-yl)-N-methyl-formamide.

Step iv

Formyl group of Intermediate Gen-3-a is removed under conditions ofgeneral synthetic method D1 to furnish Intermediate Gen-4-a(6-bromo-2-ethyl-8-fluoro-imidazo[1,2-a]pyridin-3-yl)-methyl-amine.

Step v

Reaction of Intermediate Gen-4-a with Intermediate Gen-12-a followinggeneral synthetic method E2 afforded Intermediate Gen-5-r2-[(6-bromo-2-ethyl-8-fluoro-imidazo[1,2-a]pyridin-3-yl)-methyl-amino]-4-(4-fluoro-phenyl)-thiazole-5-carbonitrile.

Step vi

Reaction of Intermediate Gen-5-r with piperazine following generalsynthetic method F1a afforded Intermediate Gen-10-m2-[(2-ethyl-8-fluoro-6-piperazin-1-yl-imidazo[1,2-a]pyridin-3-yl)-methyl-amino]-4-(4-fluoro-phenyl)-thiazole-5-carbonitrile.

Step vii

Alkylation of Intermediate Gen-10-m with Intermediate Gen-13-a followinggeneral synthetic method F8 gave compound 12.

2.10. Compound 13:2-(4-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethyl-8-fluoroimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-N-methylacetamide

Compounds 13 listed in the table of compounds is prepared similarly ascompound 12 following general synthetic method F8 using IntermediatesGen-10-m and 2-chloro-N-methylacetamide.

2.11. Compound 14:2-(4-(2-ethyl-8-fluoro-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone

Step i

Intermediate Gen-5-a(6-bromo-2-ethyl-8-fluoro-imidazo[1,2-a]pyridin-3-yl)-[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amineis prepared from Intermediate Gen-4-a and 2-bromo-4′-fluoroacetophenonefollowing general synthetic method E1.

Step ii

Intermediate Gen-10-1(2-ethyl-8-fluoro-6-piperazin-1-yl-imidazo[1,2-a]pyridin-3-yl)-[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amineis prepared from Intermediate Gen-5-a and piperazine following generalsynthetic method Fla.

Step iii

Compound 14 is obtained by alkylation of Intermediate Gen-10-1 withIntermediate Gen-13-a following general synthetic method F8.

2.12. Compounds 15-16

Compounds 15-16 listed in the table of compounds are prepared similarlyas compound 7 following general synthetic method F8 using IntermediatesGen-10-1, Gen-13-g, Gen-13-h listed in the table of syntheticIntermediates.

2.13. Compound 17:2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-7-methylimidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone

Step i)N-(6-Bromo-2-ethyl-7-methyl-imidazo[1,2-a]pyridin-3-yl)-formamide

Intermediate Gen-2-hN-(6-Bromo-2-ethyl-7-methyl-imidazo[1,2-a]pyridin-3-yl)-formamide isprepared from 2-amino-4-bromo-5-methylpyridine and propionaldehydefollowing general synthetic method B1.

Step ii)N-(6-Bromo-2-ethyl-7-methyl-imidazo[1,2-a]pyridin-3-yl)-N-methyl-formamide

Intermediate Gen-2-h is methylated with iodomethane following generalmethod C2 to give Intermediate Gen-3-i.

Step iii)4-[2-Ethyl-3-(formyl-methyl-amino)-7-methyl-imidazo[1,2-a]pyridin-6-yl]-piperidine-1-carboxylicacid tert-butyl ester

Negishi coupling of Gen-3-i with N-boc-4-iodopiperidine derivedorganozinc reagent following general synthetic method F3 affordedIntermediate Gen-8-f.

Step iv)4-(2-Ethyl-7-methyl-3-methylamino-imidazo[(1,2-a]pyridin-6-yl)-piperidine-1-carboxylicacid tert-butyl ester

Removal of formyl and boc groups of Intermediate Gen-8-f and protectionof piperidine with Boc group is achieved under conditions of generalsynthetic methods D1 and F7 to furnish Intermediate Gen-9-g.

Step v)(2-Ethyl-7-methyl-6-piperidin-4-yl-imidazo[1,2-a]pyridin-3-yl)-[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amine

Intermediate Gen-10-s is prepared from Intermediate Gen-9-g and2-bromo-4′-fluoroacetophenone under conditions of general syntheticmethod E1 followed by boc removal with general synthetic method F5b.

Step vi)2-[4-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-7-methyl-imidazo[1,2-a]pyridin-6-yl)-piperidin-1-yl]-1-(3-hydroxy-azetidin-1-yl)-ethanone

Alkylation of Intermediate Gen-10-s with Intermediate Gen-13-a followinggeneral synthetic method F8 gave compound 17.

2.14. Compound 18:2-[(2-Ethyl-7-fluoro-6-{4-[2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-imidazo[1,2-a]pyridin-3-yl)-methyl-amino]-4-(4-fluoro-phenyl)-thiazole-5-carbonitrile

Step i

Intermediate Gen-1-b is prepared from 2-amino-4-fluoropyridine followinggeneral synthetic method A.

Step ii

Intermediate Gen-2-i is prepared from Intermediate Gen-1-b andpropionaldehyde following general synthetic method B1.

Step iii

Intermediate Gen-2-i is methylated with iodomethane following generalmethod C1 to give Intermediate Gen-3-j.

Step iv

Formyl group of Intermediate Gen-3-j is removed under conditions ofgeneral synthetic method D2 to furnish Intermediate Gen-4-g.

Step v

Reaction of Intermediate Gen-4-g with Intermediate Gen-12-a followinggeneral synthetic method E2 afforded Intermediate Gen-5-u.

Step vi

Reaction of Intermediate Gen-5-u with piperazine following generalsynthetic method F1a afforded Intermediate Gen-10-r.

Step vii

Alkylation of Intermediate Gen-10-r with Intermediate Gen-13-a followinggeneral synthetic method F8 gave compound 18.

2.15. Compound 24:2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone

Step i

Intermediate Gen-5-b(6-Bromo-2-ethyl-imidazo[1,2-a]pyridin-3-yl)-[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amineis prepared from Gen-4-b(6-Bromo-2-ethyl-imidazo[1,2-a]pyridin-3-yl)-methyl-amine and2-Bromo-4′-fluoroacetophenone following general synthetic method E1.

Step ii

Reaction of Intermediate Gen-5-b with piperazine following generalsynthetic method F1a afforded Intermediate Gen-10-e2-Ethyl-6-piperazin-1-yl-imidazo[1,2-a]pyridin-3-yl)-[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amine.

Step iii

Alkylation of Intermediate Gen-10-e with Intermediate Gen-13-a followinggeneral synthetic method F8 give compound 24.

2.16. Compounds 25 to 41

These compounds listed in Table II are prepared similarly as compound 24following general synthetic method F8 using Intermediates Gen-10-e andrespectively Intermediates Gen-13-g, Gen-13-h, Gen-13-j, Gen-13-d,Gen-13-e, Gen-13-f, 1-(Chloroacetyl)pyrrolidine, Gen-13-1,2-Chloroacetamide, Gen-13-c, 2-Chloro-N,N-dimethyl-acetamide, ethyl2-chloroacetate, Ethyl 2-Chloropropionate, Chloroacetonitrile,5-(chloromethyl)-1-cyclopropyl-1H-tetrazole, 2-Chloromethyl-oxazole,3-(Chloromethyl)-1,2,4-oxadiazole.

2.17. Compound 43: 2-hydroxyethyl4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazine-1-carboxylate

The compound 43 is prepared similarly as compound 24 until theIntermediate Gen-10-e

TEA (89 μL, 0.64 mmol, 3 eq.) and potassium carbonate (88 mg, 0.64 mmol,3 eq.) were added to a solution of hydrochloride salt of Gen-10-e (100mg, 0.21 mmol, 1 eq.) in DCM (3 mL) followed by ethylene carbonate (28mg, 0.32 mmol, 1.5 eq.). The reaction mixture was stirred at r.t. for 18h. Then DMF (1 mL) was added and the reaction was stirred at 80° C. for15 h. The reaction was quenched by addition of water. The mixture wasextracted with DCM, combined organic layers were dried over sodiumsulfate, filtered and evaporated. The crude product was purified bychromatography on silica gel (elution with DCM/MeOH 100/0 to 98/2) toafford Compound 43.

¹H NMR (400 MHz, MeOD-d₄) δ ppm 7.89 (2H, dd), 7.50-7.34 (3H, m),7.16-7.05 (2H, m), 6.94 (1H, s), 4.17-4.10 (2H, m), 3.74-3.67 (2H, m),3.68-3.57 (7H, m), 3.14-2.98 (4H, m), 2.69 (2H, q), 1.30 (3H, t)

LC-MS: MW (calcd): 524; m/z MW. (obsd): 525 (M+1).

2.18. Compound 61:2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-ylsulfonyl)acetamide

Step i

To a solution of chlorosulfonylacetyl chloride (419 μL, 3.955 mmol, 1eq.) in Et₂O (4 mL), at 0° C. was added MeOH (160 μL, 3.955 mmol, 1eq.). The reaction mixture is stirred at 0° C. for 3 h, thenconcentrated in vacuo to give chlorosulfonyl-acetic acid methyl ester.

Step ii

Compound 60 was obtained by reaction of intermediate Gen-10-e withchlorosulfonyl-acetic acid methyl ester following general syntheticmethods F11 and F13.

Step iii

To a solution of compound 60 (38 mg, 0.068 mmol, 1 eq.) in DCM (3 mL)and THF (2 mL) were added HOBT (11 mg, 0.082 mmol, 1.2 eq.) and EDC.HCl(14 mg, 0.075 mmol, 1.1 eq.). The reaction mixture was stirred at r.t.for 1.25 h then a solution of ammoniac 7 M in MeOH (2 drops) was added.The reaction mixture was stirred at r.t. for 30 min., then filtered oncelite and the filtrate was concentrated in vacuo. The residue waspurified by preparative HPLC to afford the compound 61.

¹H NMR (400 MHz, CDCl₃) δ ppm 7.88-7.85 (2H, m), 7.62 (1H, d), 7.23 (1H,d), 7.17-7.07 (3H, m), 6.70 (1H, s), 6.51 (1H, bs) NH, 5.68 (1H, bs) NH,3.90 (2H, s), 3.61 (3H, s), 3.56-3.51 (4H, m), 3.18-3.06 (4H, m), 2.75(2H, q), 1.34 (3H, t)

LC-MS: MW (calcd): 557; m/z MW. (obsd): 558 (M+1).

2.19. Compound 64: ethyl2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-3-oxopiperazin-1-yl)acetate

Compound 64 is prepared from Intermediate Gen-5-b and3-Oxo-piperazine-1-carboxylic acid tert-butyl ester using the method F4,following by the method F5b to give1-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-a]pyridin-6-yl)-piperazin-2-one(Gen-10-d).

To a solution of Gen-10-d (60 mg, 0.133 mmol, 1 eq.) in 4 mL of DMF atr.t. was added NaH 60% in oil (8 mg, 0.199 mmol, 1.5 eq.). The reactionmixture was stirred for 1 h at r.t. then ethyl bromo acetate (0.018 mL,0.159 mmol, 1.2 eq.) was added. The reaction mixture was stirred at r.t.for 2 h. The reaction mixture was quenched with a saturated solution ofammonium chloride. The aqueous phase was extracted with AcOEt. Thecombined organic layers were washed with a saturated solution of sodiumcarbonate, with brine, dried over Na₂SO₄, filtered and concentrated invacuo. The crude product was purified by chromatography on silica gel toafford Compound 64.

LC-MS: MW (calcd): 536; m/z MW. (obsd): 537 (M+1).

2.20. Compound 76:4-(2-ethyl-3-((4-(4-chlorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-3,6-dihydro-2H-thiopyran 1,1-dioxide

Compound 76 is prepared from Intermediate Gen-5-i and2-(3,6-Dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolaneusing method F2 to give4-(2-ethyl-3-((4-(4-chlorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-3,6-dihydro-2H-thiopyran(Gen-10-g).

Oxone tetrabutylammonium salt (489 mg, 0.3 mmol, 1.5 eq.) was added to asolution of4-(2-ethyl-3-((4-(4-chlorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-3,6-dihydro-2H-thiopyranGen-10-g (93.5 mg, 0.2 mmol, 1 eq.) in DCM (1.1 mL). The reactionmixture was stirred at r.t. for 4 h, then brine was added and layerswere separated. The aqueous layer was extracted with dichloromethane,then combined organic layers were dried over sodium sulfate, filteredand evaporated. The crude product was purified by chromatography onsilica gel (elution with DCM/MeOH 100/0 to 98/2) to afford Compound 76.

¹H NMR (400 MHz, CDCl₃) δ ppm 7.81 (2H, d), 7.77 (1H, bs), 7.61 (1H, d),7.37 (2H, d), 7.29 (1H, d), 6.76 (1H, s), 5.90 (1H, t), 3.79 (2H, bs),3.63 (3H, s), 3.26-3.20 (2H, m), 3.15-3.07 (2H, m), 2.77 (2H, q), 1.35(3H, t)

LC-MS: MW (calcd): 498 (³⁵Cl), 500 (³⁷Cl); m/z MW. (obsd): 499 (³⁵ClM+1), 501 (³⁷Cl M+1).

2.21. Compound 78: tert-butyl4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-3-hydroxypiperidine-1-carboxylate

Compound 78 is prepared from Intermediate Gen-5-c and4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-piperidine-1-carboxylicacid tert-butyl ester using method F2 to give4-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-a]pyridin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester.

To a solution of4-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-a]pyridin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (0.15 g, 0.28 mmol, 1 eq.) in 6 mL of THF at 0° C.under nitrogen was added BH₃.THF 1 M in THF (2.81 mL, 2.81 mmol, 10eq.). The reaction mixture was stirred at 0° C. for 4 h, then at r.t.for 14 h. The reaction mixture was cooled to 0° C., then NaOH 2 M (6 mL)and H₂O₂30% aqueous (6 mL) were added. The reaction mixture was refluxedfor 3 h then cooled to r.t. and THF was removed in vacuo. The remainingaqueous phase was extracted with DCM three times. The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by chromatographyon silica gel (elution with heptane/EtOAc: 100/0 to 40/60) to affordCompound 78.

¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.04 (1H, d), 7.96-7.92 (2H, m),7.65-7.61 (1H, m), 7.57-7.54 (1H, m), 7.10 (2H, t), 7.03 (1H, s),4.37-4.33 (1H, m), 4.19-4.16 (1H, m), 3.75-3.61 (4H, m), 2.91-2.78 (3H,m), 2.73-2.60 (2H, m), 1.91-1.66 (2H, m), 1.52 (9H, d), 1.39 (3H, t)

LC-MS: MW (calcd): 551; m/z MW. (obsd): 552 (M+1).

2.22. Compound 90:N-(6-(1-(3-aminopropylsulfonyl)piperidin-4-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine

Step i

Reaction of Intermediate Gen-10-c and 3-chloro-propane-1-sulfonylchloride following method F11 then general synthetic method F12a withphtalimide afforded Intermediate Gen-10-p.

Step ii){6-[1-(3-Amino-propane-1-sulfonyl)-piperidin-4-yl]-2-ethyl-imidazo[1,2-a]pyridin-3-yl}-[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amine

To a solution of Intermediate Gen-10-p (0.053 g, 0.077 mmol, 1 eq.) in 4mL of EtOH at r.t. was added hydrazine hydrate (0.013 mL, 0.270 mmol,3.5 eq.). The reaction mixture was stirred 2 h at 90° C. and at r.t.overnight. The reaction mixture was concentrated in vacuo. The residuewas taken up with DCM and a saturated Na₂CO₃ solution. The aqueous phasewas extracted with DCM. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated in vacuo. The crudeproduct was purified by chromatography on silica gel (elution withDCM/MeOH) to afford Compound 90.

¹H NMR (300 MHz, CDCl₃) δ ppm 7.85 (2H, dd), 7.61 (1H, s), 7.57 (1H, d),7.19-7.02 (3H, m), 6.67 (1H, s), 3.92 (2H, bd), 3.61 (3H, s), 3.16-3.02(1H, m), 3.01-2.69 (7H, m), 2.68-2.51 (1H, m), 2.11-1.97 (2H, m),1.96-1.87 (2H, m), 1.86-1.66 (2H, m), 1.34 (3H, t)

LC-MS: MW (calcd): 556; m/z MW. (obsd): 557 (M+1).

2.23. Compound 91:N-(2-ethyl-6-(1-(2-morpholinoethylsulfonyl)piperidin-4yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine

To a solution of Gen-10-y (0.026 g, 0.049 mmol, 1 eq.) in 2 mL of MeCNat r.t. was added morpholine (0.013 mL, 0.148 mmol, 3 eq.). The reactionmixture was stirred for 45 min at r.t. then ethyl bromo acetate (0.009mL, 0.079 mmol, 1.2 eq.) was added. The reaction mixture was stirred at90° C. for 4.5 h and at r.t. overnight. The reaction mixture wasconcentrated in vacuo. The crude product was purified by chromatographyon silica gel (elution with DCM/MeOH: 100/0 to 98/2) to afford Compound91.

¹H NMR (400 MHz, MeOD-d₄) δ ppm 7.99-7.81 (3H, m), 7.51 (2H, dd), 7.10(2H, t), 6.96 (1H, s), 3.84 (2H, d), 3.75-3.58 (7H, m), 3.24 (2H, t),2.95 (2H, t), 2.89-2.66 (5H, m), 2.55 (4H, bs), 1.92 (2H, d), 1.85-1.67(2H, m), 1.32 (3H, t)

LC-MS: MW (calcd): 612; m/z MW. (obsd): 613 (M+1).

2.24. Compound 92:4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidine-1-sulfonamide

To a solution of Gen-10-c (0.05 g, 0.115 mmol, 1 eq.) in dioxane (2 mL)was added sulfamide (0.039 g, 0.402 mmol, 3.5 eq.). The reaction mixturewas heated at 110° C. under microwave irradiation for 45 min. Aftercooling, water and EtOAc were added to the reaction mixture, the aqueouslayer was extracted with EtOAc twice. The combined organic layers werewashed with water and brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by chromatography onsilica gel to afford Compound 92.

¹H NMR (400 MHz, MeOD-d₄) δ ppm 7.93-7.84 (3H, m), 7.53 (1H, dd), 7.40(1H, dd), 7.11 (2H, t), 6.94 (1H, s), 3.75 (2H, d), 3.62 (3H, s),2.76-2.66 (5H, m), 1.90 (2H, bd), 1.83 (2H, qd), 1.32 (3H, t)

LC-MS: MW (calcd): 514; m/z MW. (obsd): 515 (M+1).

2.25. Compound 105:1-(2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazol-5-yl)ethanone

To a solution of Compound 104 (0.06 g, 0.11 mmol, 1 eq.) in 2 mL of THFat −78° C. under argon was added MeLi 1.6 M in Et₂O (0.1 mL, 0.16 mmol,1.45 eq.) dropwise. The reaction mixture was stirred at −78° C. for 1 h,then warmed up to r.t. and stirred for 4 d. The reaction mixture wasquenched with a saturated solution of ammonium chloride, the aqueousphase was extracted with AcOEt. The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated in vacuo. Thecrude product was purified by preparative HPLC to afford Compound 105.

¹H NMR (400 MHz, MeOD-d₄) δ ppm 7.96 (1H, s), 7.69-7.60 (2H, m), 7.55(1H, d), 7.44 (1H, dd), 7.23 (2H, t), 3.85 (2H, d), 3.59 (3H, s),2.91-2.81 (5H, m), 2.80-2.68 (3H, m), 2.00 (3H, s), 1.99-1.92 (2H, m),1.91-1.77 (2H, m), 1.33 (3H, t)

LC-MS: MW (calcd): 555; m/z MW. (obsd): 556 (M+1).

2.26. Compound 106:N-(2-(2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorophenyl)acetamide

To Intermediate Gen-10-al (0.07 g, 0.118 mmol, 1 eq.), acetamide (0.009g, 0.141 mmol, 1.2 eq.), cesium carbonate (0.054 g, 0.165 mmol, 1.4eq.), Xantphos (0.010 g, 0.017 mmol, 0.15 eq.) and Pd₂(dba)₃ (0.006 g,0.006 mmol, 0.05 eq.) in a sealed tube under argon was added degasseddioxane. The reaction mixture was heated at 100° C. for 6 h. Aftercooling to r.t., the reaction mixture was filtered on Celpure® P65 andthe residue is washed with EtOAc. The filtrate was concentrated in vacuoand the crude product was purified by chromatography on silica gel(elution with DCM/MeOH) to afford Compound 106.

¹H NMR (400 MHz, CDCl₃) δ ppm 11.56 (1H, bs), 8.43 (1H, d), 7.66 (1H,d), 7.61 (1H, s), 7.55 (1H, dd), 7.22 (1H, d), 6.84-6.73 (2H, m), 3.96(2H, d), 3.63 (3H, s), 2.87-2.71 (7H, m), 2.71-2.54 (1H, m), 2.09 (3H,s), 2.02-1.92 (2H, m), 1.91-1.77 (2H, m), 1.37 (3H, t)

LC-MS: MW (calcd): 570; m/z MW. (obsd): 571 (M+1).

2.27. Compound 107:(2-(2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorophenyl)methanol

To a solution of Intermediate Gen-10-al (0.050 g, 0.084 mmol, 1 eq.) in0.84 mL of THF at −78° C. under argon was added iPrMgCl.LiCl 1.3 M inTHF (0.32 mL, 0.421 mmol, 5 eq.) dropwise. The reaction mixture waswarmed up from −78° C. to 0° C. over 1 h, then was added iPrMgCl.LiCl1.3 M in THF (0.32 mL, 0.421 mmol, 5 eq.). The reaction mixture waswarmed up to r.t. and stirred for 1.5 h. At this point, paraformaldehyde(0.025 g, 0.843 mmol, 10 eq.) was added and the reaction mixture wasleft under stirring overnight. The reaction mixture was quenched with asaturated solution of ammonium chloride and then filtered on celite. Thetwo phases of the filtrate were separated. The aqueous phase wasextracted with EtOAc. The combined organic layers were washed withbrine, dried over MgSO₄, filtered and concentrated in vacuo. The crudeproduct was purified by preparative HPLC to afford Compound 107.

¹H NMR (300 MHz, CDCl₃) δ ppm 7.61 (2H, dd), 7.53 (1H, dd), 7.17 (2H,td), 7.05 (1H, td), 6.64 (1H, s), 4.60 (2H, d), 3.97 (2H, d), 3.58 (3H,s), 2.87-2.59 (8H, m), 2.05-1.76 (4H, m), 1.36 (3H, t)

LC-MS: MW (calcd): 543; m/z MW. (obsd): 544 (M+1).

2.28. Compound 137:2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carboxamide

A solution of compound 136 (0.050 g, 0.093 mmol, 1 eq.) in H₂SO₄ (208μL, 3.90 mmol, 42 eq.) was stirred at r.t. overnight. Then water wasadded to the reaction mixture water, and the reaction was neutralizedwith a saturated NaHCO₃ solution. The crude product was filtered andwashed with water twice. The solid obtained was dried in vacuo for 48 hto afford Compound 137.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.10 (1H, s), 7.75 (2H, t), 7.54 (1H,d), 7.36 (1H, d), 7.25 (2H, t), 3.68 (2H, d), 3.50 (3H, s), 3.30 (2H, s)NH2, 2.89 (3H, s), 2.82-2.71 (3H, m), 2.63 (2H, q), 1.92-1.83 (2H, m),1.81-1.71 (2H, m), 1.25 (3H, t) LC-MS: MW (calcd): 556; m/z MW. (obsd):557 (M+1).

2.29. Compound 174:2-(4-(2-(2-cyanoethyl)-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-N,N-dimethylacetamide

Step i

Reaction of 2-amino-5-bromo-pyridine with Z-cinnamaldehyde according togeneral method B1 afforded Intermediate Gen-2-g(E)-N-(6-bromo-2-styrylimidazo[1,2-a]pyridin-3-yl)-formamide.

Step ii

Methylation of Intermediate Gen-2-g following general method C1 led toIntermediate Gen-3-g(E)-N-(6-bromo-2-styrylimidazo[1,2-a]pyridin-3-yl)-N-methylformamide.

LC-MS: MW (calcd): 355 (⁷⁹Br), 357 (⁸¹Br); m/z. (obsd): 356 (⁷⁹Br M+1),358 (⁸¹Br M+1).

Step iii

Deformylation of Intermediate Gen-3-g is performed according to methodD1 to give Intermediate Gen-4-f(E)-6-bromo-N-methyl-2-styrylimidazo[1,2-a]pyridin-3-amine.

LC-MS: MW (calcd): 327 (⁷⁹Br), 329 (⁸¹Br); m/z. (obsd): 328 (⁷⁹Br M+1),330 (⁸¹Br M+1).

Step iv

Intermediate Gen-4-f is reacted with 2-bromo-1-(4-fluorophenyl)ethanoneaccording to general method E1 to lead to Intermediate Gen-5-p(E)-N-(6-bromo-2-styrylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine.

LC-MS: MW (calcd): 504 (⁷⁹Br), 506 (⁸¹Br); m/z. (obsd): 505 (⁷⁹Br M+1),507 (⁸¹Br M+1).

Step v

Step i

To a solution of Intermediate Gen-5-p (16.2 g, 32.1 mmol, 1 eq.) in DCM(500 mL) cooled at 3° C. was added Osmium tetroxide (in t-BuOH, 14.6 g,1.44 mmol, 0.045 eq.). N-methylmorpholine-4-oxide (8.6 g, 63.6 mmol, 2eq.) was added and the reaction kept stirring. After 20 min anadditional portion of N-methylmorpholine-4-oxide (4.3 g, 31.8 mmol, 1eq.) was added, this operation was performed 7 times (until completeconversion of starting material was observed). The reaction was quenchedby addition of water (500 mL). Layers were separated and the aqueouslayer was extracted with DCM (2×100 mL). The combined organic layerswere dried over sodium sulfate, filtered and concentrated. The crudeproduct was purified by chromatography on silica gel (elution withDCM/MeOH 99.5/0.5 to 95/5) to give Intermediate Gen-5-q(6-bromo-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridine-2-carbaldehyde)and Gen-5-ab1-(6-bromo-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-2-yl)-2-phenylethane-1,2-diol.

Gen-5-q LC-MS: MW (calcd): 430 (⁷⁹Br), 432 (⁸¹Br); m/z. (obsd): 431(⁷⁹Br M+1), 433 (⁸¹Br M+1).

Gen-5-ab LC-MS: MW (calcd): 538 (⁷⁹Br), 540 (⁸¹Br); m/z. (obsd): 539(⁷⁹Br M+1), 541 (⁸¹Br M+1).

Step ii

A solution of1-(6-bromo-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-2-yl)-2-phenylethane-1,2-diol(Gen-5-ab) (10.8 g, 20 mmol, 1 eq.) in DCM (500 mL) was cooled to −4° C.Lead tetraacetate (dried before use, 13.3 g, 30 mmol, 1.5 eq.) was addedand stirred at −4° C. for 0.5 h. The reaction was quenched by additionof water (500 mL). The mixture was filtered and the layers in thefiltrate were separated. The aqueous layer was extracted with DCM (2×200mL). The combined organic layers were dried over sodium sulfate,filtered and concentrated. The crude product was purified bychromatography on silica gel (elution with heptane/EtOAc 100/0 to 50/50)to give an additional amount of Intermediate Gen-5-q6-bromo-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridine-2-carbaldehyde.

LC-MS: MW (calcd): 430 (⁷⁹Br), 432 (⁸¹Br); m/z. (obsd): 431 (⁷⁹Br M+1),433 (⁸¹Br M+1).

Step iii

Sodium hydride (60% in oil suspension, 55.2 mg, 1.38 mmol, 1.15 eq.) wasadded to a solution of diethyl cyanomethylphosphonate (234 mg, 1.32mmol, 1.1 eq.) in anhydrous THF (5 mL). The resulting white suspensionwas stirred for 10 min at room temperature and then cooled to −78° C.Intermediate Gen-5-q (518 mg, 1.2 mmol, 1 eq.) dissolved in anhydrousTHF (10 mL) was added with a syringe pump at a rate of 60 mL/h. Themixture was stirred for 0.5 h at −78° C., then allowed to warm to roomtemperature and stirred for additional 20 min. The reaction mixture wasquenched by addition of water (100 mL) and extracted with EtOAc (3×30mL). The organic layers were combined, dried over sodium sulfate,filtered and concentrated. The crude product was purified bychromatography on silica gel (elution with heptanes/EtOAc 70/30 to65/35) to give3-(6-bromo-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridine-2-yl)acrylonitrile(Gen-5-ac).

LC-MS: MW (calcd): 453 (⁷⁹Br), 455 (⁸¹Br); m/z. (obsd): 454 (⁷⁹Br M+1),456 (⁸¹Br M+1).

Step vii

Suzuki coupling of3-(6-bromo-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridine-2-yl)acrylonitrile(Gen-5-ac) with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate according to generalmethod F2 afforded tert-butyl4-(2-(2-cyanovinyl)-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridine-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate.

LC-MS: MW (calcd): 556; MW. (obsd): 557 (M+1).

Step viii

Reduction of the latter compound is performed according to generalmethod F6 in presence of a catalytic amount of acetic acid to givetert-butyl4-(2-(2-cyanoethyl)-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-aa.]pyridine-6-yl)piperidine-1-carboxylate.

LC-MS: MW (calcd): 560; m/z. (obsd): 561 (M+1).

Boc deprotection of the latter compound is performed according togeneral method F5b to afford Intermediate Gen-10-aa.

LC-MS: MW (calcd): 460; m/z. (obsd): 461 (M+1).

Step x

Intermediate Gen-10-aa is alkylated with 2-chloro-N,N-dimethylacetamideusing general method F8 to give the expected compound 174.

2.30. Compound 175:3-(3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)amino)-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-2-yl)propanenitrileStep i

Intermediate Gen-10-aa is sulfonylated with methanesulfonyl chlorideusing general method F11 to give3-(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-2-yl)propanenitrile.

LC-MS: MW (calcd): 538; m/z. (obsd): 539 (M+1).

Step ii

The latter compound is reacted under conditions of general method F14 togive the expected compound 175.

2.31. Compound 176:3-(6-(1-(2-(dimethylamino)-2-oxoethyl)piperidin-4-yl)-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-2-yl)propanamide Step i

Sodium hydride (60% in oil suspension, 92 mg, 2.3 mmol, 1.15 eq.) wasadded to a solution of methyl 2-(dimethoxyphosphoryl)acetate (401 mg,2.2 mmol, 1.1 eq.) in anhydrous THF (20 mL). The resulting whitesuspension was stirred for 20 min at room temperature and then cooled to−78° C. Intermediate Gen-5-q (863 mg, 2.0 mmol, 1 eq.) dissolved inanhydrous THF (15 mL) was added with a syringe pump at a rate of 45mL/h. The mixture was stirred for 50 min at −78° C., then allowed towarm to room temperature and stirred for additional 40 min. The reactionmixture was evaporated. Brine (50 mL) was added to the crude product andthe mixture was extracted with EtOAc (3×50 mL). The organic layers werecombined, dried over sodium sulfate, filtered and concentrated. Thecrude product was purified by chromatography on silica gel (elution withheptanes/EtOAc 100/0 to 50/50) to give the Intermediate Gen-5-ad.

LC-MS: MW (calcd): 486 (⁷⁹Br), 488 (⁸¹Br); m/z. (obsd): 487 (⁷⁹Br M+1),489 (⁸¹Br M+1).

Step ii

Suzuki coupling of methyl3-(6-bromo-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-2-yl)acrylatewith tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate according to generalmethod F2 afforded tert-butyl4-(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-(3-methoxy-3-oxoprop-1-enyl)imidazo[1,2-a]pyridin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate.

LC-MS: MW (calcd): 589; MW. (obsd): 590 (M+1).

Step iii

Reduction of the latter compound is performed according to generalmethod F6 in presence of a catalytic amount of acetic acid to givetert-butyl4-(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-(3-methoxy-3-oxopropyl)imidazo[1,2-a]pyridin-6-yl)piperidine-1-carboxylate.

LC-MS: MW (calcd): 593; m/z. (obsd): 594 (M+1).

Step iv

The latter compound is saponified according to general method F13 toafford3-(6-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-2-yl)propanoicacid.

LC-MS: MW (calcd): 579; m/z. (obsd): 580 (M+1).

Step v

A solution of3-(6-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-2-yl)propanoicacid (220 mg, 0.38 mmol, 1 eq.) and TEA (211 μL, 1.52 mmol, 4 eq.) inDMF (3 mL) was stirred for 10 min at r.t. Propane phosphonic acidanhydride (226 μL, 0.76 mmol, 2 eq.) followed by ammonium chloride (40.7mg, 0.76 mmol, 2 eq.) were added and the resulting mixture was stirredat r.t. for 4 days. TEA (211 μL, 1.52 mmol, 4 eq.), propane phosphonicacid anhydride (226 μL, 0.76 mmol, 2 eq.) and ammonium chloride (40.7mg, 0.76 mmol, 2 eq.) were added and the reaction mixture kept stirringfor 2 h. Brine was added (100 mL) and the mixture was extracted with DCM(3×20 mL). The organic layers were combined, dried over sodium sulfate,filtered and concentrated. The crude product was purified bychromatography on silica gel (elution with DCM/MeOH 100/0 to 80/20) togive tert-butyl4-(2-(3-amino-3-oxopropyl)-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidine-1-carboxylate(Gen-10-am).

LC-MS: MW (calcd): 578; m/z. (obsd): 579 (M+1).

Step vi

Boc deprotection of the latter compound is performed according togeneral method F5b to afford3-(3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-6-(piperidin-4-yl)imidazo[1,2-a]pyridin-2-yl)propanamide.

LC-MS: MW (calcd): 478; m/z. (obsd): 479 (M+1).

Step vii

The latter compound was alkylated with 2-chloro-N,N-dimethylacetamideusing general method F8 to give the expected compound 176.

2.32. Compound 184: ethyl2-(3-(3-((4-(4-chlorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)-2-oxoimidazolidin-1-yl)acetate

To a solution of Gen-10-a (0.30 g, 0.066 mmol, 1 eq.) in 3 mL of DMF atr.t. was added NaH 60% in oil (0.004 g, 0.099 mmol, 1.5 eq.). Thereaction mixture was stirred 45 min at r.t. then ethyl bromo acetate(0.009 mL, 0.079 mmol, 1.2 eq.) was added. The reaction mixture wasstirred at r.t. for 1 h. The reaction mixture was quenched with asaturated solution of ammonium chloride. The aqueous phase was extractedwith AcOEt. The combined organic layers were washed with a saturatedsolution of sodium carbonate, with brine, dried over Na₂SO₄, filteredand concentrated in vacuo. The crude product was purified bychromatography on silica gel (elution with Heptane/AcOEt: 100/0 to50/50) to afford Compound 184.

¹H NMR (400 MHz, MeOD) δ ppm 8.39-8.28 (1H, m), 7.84 (2H, d), 7.71 (1H,dd), 7.57 (1H, dd), 7.40-7.33 (2H, m), 7.00 (1H, s), 4.18 (2H, q), 4.01(2H, s), 3.93-3.86 (2H, m), 3.67-3.57 (5H, m), 2.72 (2H, q), 1.31 (3H,t), 1.25 (3H, t)

LC-MS: MW (calcd): 538 (³⁵Cl), 540 (³⁷Cl); m/z MW. (obsd): 539 (³⁵ClM+1), 541 (³⁷Cl M+1).

2.33. Compound 186:2-(2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazol-5-yl)acetonitrile

To a solution of compound 147 (50 mg, 0.092 mmol, 1 eq.) with triphenylphosphine (60 mg, 0.23 mmol, 2.5 eq.) in THF (1.5 mL) at 0° C. wereadded acetone cyanohydrine (23 mg, 0.27 mmol, 3 eq.) and DEAD (40 mg,0.23 mmol, 2.5 eq.). The reaction mixture was stirred at 0° C. for 3 h,then quenched by addition of a saturated NaHCO₃ solution and EtOAc. Theorganic layer was washed with a saturated NaHCO₃ solution, water, andbrine, dried over Na₂SO₄, filtered and concentrated in vacuo. The crudeproduct was purified by preparative HPLC to afford Compound 186.

¹H NMR (400 MHz, CDCl₃) δ ppm 7.64-7.57 (4H, m), 7.22-7.14 (3H, m), 3.97(2H, d), 3.72 (2H, d), 3.56 (3H, s), 2.85-2.72 (7H, m), 2.71-2.60 (1H,m), 2.06-1.95 (2H, m), 1.86 (2H, qd), 1.37 (3H, t)

LC-MS: MW (calcd): 552; m/z. (obsd): 553 (M+1).

2.34. Compound 187:2-ethyl-N-(4-(4-fluorophenyl)pyrimidin-2-yl)-N-methyl-6-(1-(methylsulfonyl)-1,2,3, 6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-amine

To Intermediate Gen-9-a (90 mg, 0.27 mmol, 1 eq.),2-chloro-4-(4-fluorophenyl)-pyrimidine (63 mg, 0.30 mmol, 1.1 eq.),cesium carbonate (0.177 g, 0.54 mmol, 2 eq.), Xantphos (0.008 g, 0.014mmol, 0.05 eq.) and palladium acetate (0.003 g, 0.009 mmol, 0.03 eq.) ina sealed tube under nitrogen was added degazed dioxane. The reactionmixture was heated at 130° C. overnight. After cooling to r.t., thereaction mixture was quenched with water. The aqueous phase wasextracted with AcOEt three times. The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated invacuo. The crude product was purified by chromatography on silica gel(elution with DCM/MeOH: 100/0 to 95/5) to afford Compound 187.

¹H NMR (300 MHz, CDCl₃) δ ppm 8.41 (1H, d), 8.05-7.90 (2H, m), 7.65-7.42(2H, m), 7.28 (1H, dd), 7.13 (3H, d), 6.03 (1H, t), 4.00-3.87 (2H, m),3.62 (3H, s), 3.47 (2H, t), 2.82 (3H, s), 2.73 (2H, q), 2.64-2.43 (2H,m), 1.28 (3H, t)

LC-MS: MW (calcd): 506; m/z MW. (obsd): 507 (M+1).

2.35. Compound 202:(1-aminocyclopropyl)(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)methanone

Step i

Intermediate Gen-10-e was reacted with Fmoc-1-amino-1-cyclopropanecarboxylic acid according to general synthetic method F9a to giveFmoc-protected derivative.

Step ii

To a solution of Fmoc-protected derivative obtained in step i) above (66mg, 0.089 mmol, 1 eq.) in a mixture of DCM/DMF (2/4 mL) were addedpyridine (100 μL, excess.) then morpholine (78 μL, 0.89 mmol, 10 eq.).The reaction mixture was stirred at r.t. for 20 h, then diluted withwater and EtOAc. The aqueous layer was extracted with EtOAc, then theorganic layer was washed with water, and brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The crude product was purified bychromatography on silica gel (elution with DCM/MeOH: 100/0 to 98/2) toafford Compound 202.

¹H NMR (300 MHz, CDCl₃) δ ppm 7.86 (2H, dd), 7.54 (1H, d), 7.24-7.04(4H, m), 6.68 (1H, s), 3.84 (4H, bt), 3.61 (3H, s), 3.04 (4H, bt), 2.73(2H, q), 1.33 (3H, t), 1.07-0.99 (2H, m), 0.86-0.77 (2H, m)

LC-MS: MW (calcd): 519; m/z. (obsd): 520 (M+1).

2.36. Compound 204:2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-2-oxoacetamideStep i

Intermediate Gen-10-e was reacted with chloro-oxo-acetic acid ethylester following successive general synthetic methods F9b and F13 to give[4-(2-ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-a]pyridin-6-yl)-piperazin-1-yl]-oxo-aceticacid (Intermediate Gen-10-an).

To a solution of Intermediate Gen-10-an (24 mg, 0.047 mmol, 1 eq.) inDCM (3 mL) and THF (2 mL) were added HOBT (8 mg, 0.057 mmol, 1.2 eq.)and EDC.HCl (10 mg, 0.075 mmol, 1.1 eq.). The reaction mixture wasstirred at r.t. for 1 h then a solution of ammoniac 7 N in MeOH (3drops) was added. The reaction mixture was stirred at r.t. for 3 h, thenfiltered on celite and the filtrate was concentrated in vacuo. Theresidue was purified by preparative HPLC to afford Compound 204.

¹H NMR (400 MHz, CDCl3) δ ppm 7.87-7.81 (2H, m), 7.53 (1H, dd), 7.20(1H, d), 7.14-7.05 (3H, m), 7.04 (1H, bs) NH, 6.66 (1H, s), 5.59 (1H,bs) NH, 4.24 (2H, t), 3.80 (2H, t), 3.59 (3H, s), 2.72 (2H, q),3.11-3.05 (4H, m), 1.33 (3H, t)

LC-MS: MW (calcd): 507; m/z MW. (obsd): 508 (M+1).

2.37. Compound 211:1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-4-olStep i

Intermediate Gen-5-c is reacted under conditions of general method F1bwith 1,4-Dioxa-8-aza-spiro[4.5]decane to give the[6-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-2-ethyl-imidazo[1,2-a]pyridin-3-yl]-[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amine(Intermediate Gen-10-ap)

Step ii

To as solution of Intermediate Gen-10-ap (162 mg, 0.33 mmol, 1 eq.) in aTHF/water (1/1) mixture (1 mL) was added HCl (6 N in water, 1 mL). Thereaction mixture was stirred at 60° C. overnight. Solvents wereevaporated, then aqueous sodium carbonate was added and the mixture wasextracted with ethyl acetate. Combined organic layers were washed withwater, dried over Na₂SO₄, filtered and concentrated. The crude productwas purified by chromatography on silica gel (elution withheptane/EtOAc: 100/0 to 0/100) to afford Intermediate Gen-10-aq

LC-MS: MW (calcd): 449; m/z. (obsd): 450 (M+1).

Step iii

To a solution of Intermediate Gen-10-aq (70 mg, 0.16 mmol, 1 eq.) inethanol (0.5 mL) stirred at 0° C. was added sodium borohydride (5 mg,0.12 mmol, 0.8 eq.). The reaction was stirred overnight allowing thetemperature to rise to room temperature. Solvent was evaporated, aqueousammonium chloride was added and the mixture was extracted with ethylacetate. The combined organic layers were dried over sodium sulfate,filtered and evaporated. Compound 211 was then obtained by purificationby preparative LC-MS.

LC-MS: MW (calcd): 451; m/z. (obsd): 452 (M+1).

2.38. Compound 222:{2-[4-(2-Ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-a]pyridin-6-yl)-piperazin-1-yl]-4,5-dihydro-oxazol-5-yl}-methanol

A solution of Intermediate Gen-10-c (300 mg, 0.69 mmol, 1 eq.),4-(chloromethyl)-1,3-oxazolidin-2-one (103 mg, 0.76 mmol, 1.1 eq.),Cs₂CO₃ (450 mg, 1.38 mmol, 2 eq.) and NaI (103 mg, 0.69 mmol, 1 eq.) inDMF (3 mL) was stirred at 90° C. overnight. Water was added and thereaction mixture was extracted with EtOAc. The combined organic layerswere dried over sodium sulfate, filtered and evaporated. The crudeproduct was purified by chromatography on silica gel (elution withDCM/MeOH: 100/0 to 90/10) and preparative HPLC to give Compound 222.

LC-MS: MW (calcd): 534; m/z. (obsd): 535 (M+1).

2.39. Compound 227:Cyclopropyl-[4-(2-ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-a]pyridin-6-yl)-piperazin-1-yl]-methanone

To a solution of Gen-10-e (200 mg, 0.423 mmol, 1 eq.) in DCM (3 mL) wereadded TEA (294 mg, 2.114 mmol, 5 eq.) followed by the 4-Bromo-butyrylchloride (73 μL, 0.634 mmol, 1.5 eq.). The reaction mixture was stirredat r.t. overnight, then was quenched with water and the aqueous layerwas extracted with DCM twice. The organic layer was washed with water,and brine, dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by chromatography on silica gel (elution withDCM/MeOH: 100/0 to 97/3) to afford the Compound 227.

LC-MS: MW (calcd): 504; m/z MW. (obsd): 505 (M+1).

2.40. Compound 229:[6-(1,1-Dioxo-isothiazolidin-2-yl)-2-ethyl-imidazo[1,2-a]pyridin-3-yl]-[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amineStep i

To a solution of ammonium chloride (440 mg, 8.23 mmol, 4 eq.) in water(10 mL) were added a solution of Gen-5-z (818 mg, 2.058 mmol, 1 eq.) inMeOH (5 mL) and THF (5 mL), followed by iron (460 mg, 8.23 mmol, 4 eq.).The reaction mixture was stirred at 70° C. for 3 h. The solvents wereevaporated. The residue was resuspended/dissolved in EtOAc/water, thismixture was filtered over Celite prior to separation. The separatedaqueous phase was extracted once more with EtOAc, The combined organicphases were dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by chromatography on silica gel (elution withDCM/MeOH: 100/0 to 95/5) to afford Intermediate Gen-5-af.

LC-MS: MW (calcd): 367; m/z MW. (obsd): 368 (M+1).

Step ii

Intermediate Gen-5-af was reacted with 3-chloro-propane-1-sulfonylchloride using general method F11 to give Intermediate3-Chloro-propane-1-sulfonic acid(2-ethyl-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-a]pyridin-6-yl)-amide(Intermediate Gen-10-ao).

LC-MS: MW (calcd): 507 (³⁵Cl), 509 (³⁷Cl); m/z MVW. (obsd): 508 (³⁵ClM+1), 510 (³⁷Cl M+1).

Step iii

To a solution of the chlorine derivative Gen-10-ao (55 mg, 0.108 mmol, 1eq.) in DMF (2 mL) was added potassium acetate (32 mg, 0.325 mmol, 3eq.), the reaction mixture was heated at 90° C. for 1 h, then at 60° C.overnight. After cooling, water and EtOAc were added to the reactionmixture, the aqueous layer was extracted with EtOAc twice. The combinedorganic layers were washed with water and brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel (elution with DCM/MeOH: 100/0 to 95/5) toafford Compound 229.

LC-MS: MW (calcd): 471; m/z MW. (obsd): 472 (M+1).

2.41. Intermediate Gen-13-j:N-[1-(2-Chloro-acetyl)-pyrrolidin-3-yl]-acetamide

To a solution of chloroacetic acid (0.715 g, 7.56 mmol, 1 eq.) in DCM(15 mL) and THF (12 mL) at r.t. was added EDC.HCl (1.89 g, 9.83 mmol,1.3 eq.) and HOBt (1.33 g, 9.83 mmol, 1.3 eq.). The reaction mixture wasstirred at r.t. for 30 min and then 3-acetamidopyrrolidine (1.26 g, 9.83mmol, 1.3 eq.) was added. After stirring two days at r.t., the reactionmixture was diluted with water, HCl 1 M, and DCM. The aqueous phase wasextracted with DCM five times. The combined organic layers were washedwith a saturated NaHCO₃ solution, with brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The resulting crude oil was used assuch in the next step.

¹H NMR (400 MHz, CDCl₃-d) δ ppm 5.33-5.01 (2H, m), 4.60-4.41 (1H, m),3.79-3.65 (2H, m), 3.63-3.44 (2H, m), 1.97 (3H, d), 1.90-1.80 (2H, m)

2.42. Intermediate Gen-11-d: 2-Bromo-1-(4-fluoro-phenyl)-d₂ ethanone

A mixture of starting material (Kolonko & Reich, 2008) (1.04 g, 7.37mmol, 1 eq.) and Br₂ immobilized on resin used in large excess indeuterated chloroform was shaken overnight at r.t. The resin wasfiltered off, washed with deuterated chloroform. The filtrate wasconcentrated in vacuo and the crude product was used directly in thenext step.

TABLE I Intermediates used towards the compounds of the invention. Int-MS Int Structures Name Mtd MW Ms'd Gen- 1-a

2-amino-5-Bromo-3- fluoropyridine A 190 (⁷⁹Br), 192 (⁸¹Br) 191 (⁷⁹Br M +1), 193 (⁸¹Br M + 1) Gen- 1-b

5-Bromo-4-fluoro- pyridin-2-ylamine A 190 (⁷⁹Br), 192 (⁸¹Br) N.A. Gen-2-a

N-(6-Bromo- 2-ethyl-8- fluoro-imidazo[1,2- a]pyridin-3-yl)- formamideGen-1-a B1 285 (⁷⁹Br), 287 (⁸¹Br) 286 (⁷⁹Br M + 1), (⁸¹Br M + 1) Gen-2-b

N-(6-Bromo-2-ethyl- imidazo[1,2-a]pyridin- 3-yl)-formamide B1 267(⁷⁹Br), 269 (⁸¹Br) 268 (⁷⁹Br M + 1), 270 (⁸¹Br M + 1) Gen- 2-c

N-(2-Ethyl-6-iodo- imidazo[1,2-a]pyridin- 3-yl)-formamide B1 315 316(M + 1) Gen- 2-d

N-(6-Bromo-2-ethyl-8- methyl-imidazo[1,2- a]pyridin-3-yl)- formamide B1or B2 281 (⁷⁹Br), 283 (⁸¹Br) 284 (⁸¹Br M + 1) Gen- 2-e

N-(6-Bromo-2- cyclopropyl- imidazo[1,2-a]pyridin- 3-yl)-formamide B2 279(⁷⁹Br), 281 (⁸¹ Br) 280 (⁷⁹Br M + 1), 282 (⁸²Br M + 1) Gen- 2-f

N-[6-Bromo-2-(2,2,2- trifluoro-ethyl)- imidazo[1,2-a]pyridin-3-yl]-formamide B1 321 (⁷⁹Br), 323 (⁸¹Br) N.A. Gen- 2-g

(E)-N-(6-bromo-2- styrylimidazo[1,2- a]pyridin-3-yl)- formamide B1 341(⁷⁹Br), 343 (⁸¹Br) N.A. Gen- 2-h

N-(6-Bromo-2-ethyl-7- methyl-imidazo[1,2- a]pyridin-3-yl)- formamide B1281 (⁷⁹Br), 283 (⁸¹Br) 282 (⁷⁹Br M + 1), 284 (⁸¹Br M + 1) Gen- 2-i

N-(6-Bromo-2-ethyl- 7-fluoro-imidazo[1,2- a]pyridin-3-yl)- formamideGen-1-b B1 285 (⁷⁹Br), 287 (⁸¹Br) 286 (⁷⁹Br M + 1) 288 (⁸¹Br M + 1) Gen-2-j

N-(2-Ethyl-6-nitro- imidazo[1,2-a]pyridin- 3-yl)-formamide B1 234 235(M + 1) Gen- 2-k

2-Ethyl-3-formylamino- imidazo[1,2-a]pyridine- 6-carboxylic acid methylester B1 247 No LC- MSN MR Gen- 3-a

N-(6-Bromo-2-ethyl-8- fluoro-imidazo[1,2- a]pyridin-3-yl)-N-methyl-formamide Gen-2-a C2 299 (⁷⁹Br), 301 (⁸¹Br) 300 (⁷⁹Br M + 1), 302(⁸¹Br M + 1) Gen- 3-b

N-(6-Bromo-2-ethyl- imidazo[1,2-a]pyridin- 3-yl)-N-methyl- formamideGen-2-b C1 281 (⁷⁹Br), 283 (⁸¹Br) 282 (⁷⁹Br M + 1), 284 (⁸¹Br M + 1)Gen- 3-c

N-(6-Bromo-2-ethyl- imidazo[1,2-a]pyridin- 3-yl)-N-(d₃-methyl)-formamide Gen-2-b C1 284 (⁷⁹Br), 286 (⁸¹Br) N.A. Gen- 3-d

N-(2-Ethyl-6-iodo- imidazo[1,2-a]pyridin- 3-yl)-N-methyl- formamideGen-2-c C1 329 330 (M + 1) Gen- 3-e

N-(6-Bromo-2-ethyl-8- methyl-imidazo[1,2- a]pyridin-3-yl)-N-methyl-formamide Gen-2-d C2 295 (⁷⁹Br), 297 (⁸¹Br) 296 (⁷⁹Br M + 1), 298(⁸¹Br M + 1) Gen- 3-f

N-(6-Bromo-2- cyclopropyl- imidazo[1,2-a]pyridin- 3-yl)-N-methyl-formamide Gen-2-e Cl 293 (⁷⁹Br), 295 (⁸¹Br) 294 (⁷⁹Br M + 1), 296 (⁸¹BrM + 1) Gen- 3-g

(E)-N-(6-bromo-2- styrylimidazo[1,2- a]pyridin-3-yl)-N- methylformamideGen-2-g C1 355 (⁷⁹Br), 357 (⁸¹Br) 356 (⁷⁹Br M + 1), 358 (⁸¹Br M + 1)Gen- 3-h

N-(6-Bromo-2-ethyl-8- methyl-imidazo[1,2- a]pyridin-3-yl)-N-ethyl-formamide Gen-2-d C2 309 (⁷⁹Br), 311 (⁸¹Br) 310 (⁷⁹Br M + 1), 312 (⁸¹BrM + 1) Gen- 3-i

N-(6-Bromo-2-ethyl-7- methyl-imidazo[1,2- a]pyridin-3-yl)-N-methyl-formamide Gen-2-h C1 295 (⁷⁹Br), 297 (⁸¹Br) 296 (⁷⁹Br M + 1), 298⁽⁸¹Br M + 1) Gen- 3-j

N-(6-Bromo-2-ethyl-7- fluoro-imidazo[1,2- a]pyridin-3-yl)-N-methyl-formamide Gen-2-i C1 299 (⁷⁹Br), 301 (⁸¹Br) 300 (⁷⁹Br M + 1), 302(⁸¹Br M + 1) Gen- 3-k

N-(2-Ethyl-6-nitro- imidazo[1,2-a]pyridin- 3-yl)-N-methyl- formamideGen-2-j C2 248 249 (M + 1) Gen- 3-l

2-Ethyl-3-(formyl- methyl-amino)- imidazo[1,2-a]pyridine- 6-carboxylicacid methyl ester Gen-2-k C1 261 262 (M + 1 Gen- 4-a

(6-Bromo-2-ethyl-8- fluoro-imidazo[1,2- a]pyridin-3-yl)-methyl- amineGen-3-a D1 271 (⁷⁹Br), 273 (⁸¹Br) 272 (⁷⁹Br M + 1), 274 (⁸¹Br M + 1)Gen- 4-b

(6-Bromo-2-ethyl- imidazo[1,2-a]pyridin- 3-yl)-methy-amine Gen-3-b D1253 (⁷⁹Br), 255 ⁽⁸¹Br) 254 (⁷⁹Br M + 1), 256 (⁸¹Br M + 1) Gen- 4-c

(2-Ethyl-6-iodo- imidazo[1,2-a]pyridin- 3-yl)-methyl-amine Gen-3-d D1301 302 (M + 1) Gen- 4-d

(6-Bromo-2-ethyl-8- methyl-imidazo[1,2- a]pyridin-3-yl)-methyl- amineGen-3-e D1 267 (⁷⁹Br), 269 (⁸¹Br) 268 (⁷⁹Br M + 1), 270 (⁸¹Br M + 1)Gen- 4-e

(6-Bromo-2- cyclopropyl- imidazo[1,2-a]pyridin- 3-yl)-methyl-amineGen-3-f D1 265 (⁷⁹Br), 267 (⁸¹Br) 266 (⁷⁹Br M + 1), 268 (⁸¹Br M + 1)Gen- 4-f

(E)-6-bromo-N-methyl- 2-styrylimidazo[1,2- a]pyridin-3-amine Gen-3-g D1327 (⁷⁹Br), 329 (⁸¹Br) 328 (⁷⁹Br M + 1), 330 (⁸¹Br M + 1) Gen- 4-g

(6-Bromo-2-ethyl-7- fluoro-imidazo[1,2- a]pyridin-3-yl)-methyl- amineGen-3-j D2 271 (⁷⁹Br), 273 (⁸¹Br) N.A. Gen- 4-h

(6-Bromo-2-ethyl-8- methyl-imidazo[1,2- a]pyridin-3-yl)-ethyl- amineGen-3-h D1 281 (⁷⁹Br), 283 (⁸¹Br) 282 (⁷⁹Br M + 1), 284 (⁸¹Br M + 1)Gen- 4-i

(2-Ethyl-6-nito- imidazo[1,2-a]pyridin- 3-yl)-methyl-amine Gen-3-k D1220 221 (M + 1) Gen- 4-j

2-Ethyl-3-methylamino- imidazo[1,2-a]pyridine- 6-carboxylic acid methylester Gen-3-l D1 233 234 (M + 1) Gen- 5-a

(6-Bromo-2-ethyl-8- fluoro-imidazo[1,2- a]pyridin-3-yl)-[4-(4-fluoro-phenyl)-thiazol- 2-yl]-methyl-amine Gen-4-a E1 448 (⁷⁹Br), 450(⁸¹Br) 449 (⁷⁹Br M + 1), 451 ⁽⁸¹Br M + 1) Gen- 5-b

(6-Bromo-2-ethyl- imidazo[1,2-a]pyridin- 3-yl)-[4-(4-fluoro-phenyl)-thiazol-2-yl]- methyl-amine Gen-4-b E1 430 (⁷⁹Br), 431 (⁸¹Br)431 (⁷⁹Br M + 1), 433 (⁸¹Br M + 1) Gen- 5-c

(2-Ethyl-6-iodo- imidazo[1,2-a]pyridin- 3-yl)-[4-(4-fluoro-phenyl)-thiazol-2-yl]- methyl-amine Gen-4-c E1 478 479 (M + 1) Gen- 5d

(6-Bromo-2-ethyl-8- methyl-imidazo[1,2- a]pyridin-3-yl)-[4-(4-fluoro-phenyl)-thiazol- 2-yl]-methyl-amine Gen-4-d E1 444 (⁷⁹Br), 446(⁸¹Br) 445 (⁷⁹Br M + 1), 447 (⁸¹Br M + 1) Gen- 5-e

2-{2-[(6-Bromo-2-ethyl- imidazo[1,2-a]pyridin- 3-yl)-methyl-amino]-thiazol-4-yl}-5-fluoro- benzonitrile Gen-4-b E1 455 (⁷⁹Br), 457 (⁸¹Br)456 (⁷⁹Br M + 1), 458 ⁽⁸¹Br M + 1) Gen- 5-f

(2-Ethyl-6-iodo- imidazo[1,2-a]pyridin- 3-yl)-[4-(4-methoxy-phenyl)-thiazol-2-yl]- methyl-amine Gen-4-c E1 490 491 (M + 1) Gen- 5-g

[4-(4-tert-Butyl-phenyl)- thiazol-2-yl]-(2-ethyl-6- iodo-imidazo[1,2-a]pyridin-3-yl)-methyl- amine Gen-4-c E1 516 517 (M + 1) Gen- 5-h

2-[(6-Bromo-2-ethyl-8- methyl-imidazo[1,2- a]pyridin-3-yl)-ethyl-amino]-4-(4-fluoro- phenyl)-thiazol-5- carbonitrile Gen-4-h E2 483(⁷⁹Br), 485 (⁸¹Br) 484 (⁷⁹Br M + 1), 486 (⁸¹Br M + 1) Gen- 5-i

4-(4-Chloro-phenyl)- thiazol-2-yl]-(2-ethyl-6- iodo-imidazo[1,2-a]pyridin-3-yl)-methyl- amine Gen-4-c E1 494 (³⁵Cl), 496 (³⁷Cl) 495(³⁵Cl M + 1) 497 (³⁷Cl M + 1) Gen- 5-j

(2-Ethyl-6-iodo- imidazo[1,2-a]pyridin- 3-yl)-methyl-[4-(4-trifluoromethoxy- phenyl)-thiazol-2-yl]- amine Gen-4-c E1 544 545(M + 1) Gen- 5-k

(2-Ethyl-6-iodo- imidazo[1,2-a]pyridin- 3-yl)-methyl-[4-(4-trifluoromethyl-phenyl)- thiazol-2-yl]-amine Gen-4-c E1 528 529 (M + 1)Gen- 5-l

[4-(3,4-Difluoro- phenyl)-thiazol-2-yl]-(2- ethyl-6-iodo-imidazo[1,2-a]pyridin- 3-yl)-methyl-amine Gen-4-c E1 496 497 (M + 1)Gen- 5-m

2-{2-[(6-Bromo-2-ethyl- imidazo[1,2-a]pyridin- 3-yl)-methyl-amino]-5-methyl-thiazol-4-yl}-5- fluoro-benzonitrile Gen-4-b E1 469 (⁷⁹Br), 471(⁸¹Br) 470 (⁷⁹Br M + 1), 472 (⁸¹Br M + 1) Gen- 5-n

(6-Bromo-2- cyclopropyl- imidazo[1,2-a]pyridin- 3-yl)-[4-(4-fluoro-3-yl)-[4-(4-fluoro- phenyl)-thiazol-2-yl]- methyl-amine Gen-4-e E1 442(⁷⁹Br), 444 (⁸¹Br) 443 (⁷⁹Br M + 1), 445 (⁸¹Br M + 1) Gen- 5-o

(6-Bromo-2-ethyl-7- fluoro-imidazo[1,2- a]pyridin-3-yl)-[4-(4-fluoro-phenyl)-thiazol- 2-yl]-methyl-amine Gen-4-g E1 448 (⁷⁹Br), 450(⁸¹Br) 449 (⁷⁹Br M + 1), 451 (⁸¹Br M + 1) Gen- 5-p

(E)-N-(6-bromo-2- styrylimidazo[1,2- a]pyridin-3-yl)-4-(4-fluorophenyl)-N- methylthiazol-2-amine Gen-4-f E1 504 (⁷⁹Br), 506 (⁸¹Br)505 (⁷⁹Br M + 1), 507 (⁸¹Br M + 1) Gen- 5-q

6-bromo-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridine-2- carbaldehyde Gen-5-ab See cpd 174 430 (⁷⁹Br),432 (⁸¹Br) 431 (⁷⁹Br M + 1), 433 (⁸¹Br M + 1) Gen- 5-r

2-[(6-Bromo-2-ethyl-8- fluoro-imidazo[1,2- a]pyridin-3-yl)-methyl-amino]-4-(4-fluoro- phenyl)-thiazole-5- carbonitrile Gen-4-a E2 473(⁷⁹Br), 475 (⁸¹Br) 474 (⁷⁹Br M + 1), 476 (⁸¹Br M + 1) Gen- 5-s

2-[(6-Bromo-2-ethyl- imidazo[1,2-a]pyridin- 3-yl)-methyl-amino]-4-(4-fluoro-phenyl)- thiazole-5-carbonitrile Gen-4-b E2 456 (⁷⁹Br), 457(⁸¹Br) 457 (⁷⁹Br M + 1), 459 (⁸¹Br M + 1) Gen- 5-t

2-[(6-Bromo-2-ethyl-8- methyl-imidazo[1,2- a]pyridin-3-yl)-methyl-amino]-4-(4-fluoro- phenyl)-thiazole-5- carbonitrile Gen-4-d E2 469(⁷⁹Br), 471 (⁸¹Br) 470 (⁷⁹Br M + 1), 472 (⁸¹Br M + 1) Gen- 5-u

2-[(6-Bromo-2-ethyl-7- fluoro-imidazo[1,2- a]pyridin-3-yl)-methyl-amino]-4-(4-fluoro- phenyl)-thiazole-5- carbonitrile Gen-4-g E2 473(⁷⁹Br), 475 (⁸¹Br) 474 (⁷⁹Br M + 1), 476 (⁸¹Br M + 1) Gen- 5-v

[6-Bromo-2-(2,2,2- trifluoro-ethyl)- imidazo[1,2-a]pyridin-3-yl]-[4-(4-chloro- phenyl)-thiazol-2-yl]- methyl-amine Gen-7-b C1 499(⁷⁹Br ³⁵Cl), 501 (⁸¹Br ³⁵Cl), ⁷⁹Br ³⁷Cl), 503 (⁸¹Br ³⁷Cl) 500 (⁷⁹Br ³⁵ClM + 1), 502 (⁸¹Br ³⁵Cl, ⁷⁹Br ³⁷Cl M + 1), 504 ⁸¹Br ³⁷Cl M + 1) Gen- 5-w

(6-Bromo-2-ethyl- imidazo[1,2-a]pyridin- 3-yl)-[3-(4-chloro- phenyl)-[1,2,4]thiadiazol-5-yl]- methyl-amine Gen-7-a Cl 447 (⁷⁹Br ³⁵Cl), 449(⁸¹Br ³⁷Cl), 451 (⁸¹Br ³⁷Cl) 448 (⁷⁹Br ³⁵Cl M + 1), 450 (⁸¹Br ³⁵Cl, ⁷⁹Br³⁷Cl M + 1), 452 (⁸¹Br ³⁷Cl M + 1) Gen- 5-x

(6-Bromo-2-ethyl- imidazo[1,2-a]pyridin- 3-yl)-[3-(4-fluoro- phenyl)-[1,2,4]thiadiazol-5-yl]- methyl-amine Gen-7-c C1 431 (⁷⁹Br), 433 (⁸¹Br)432 (⁷⁹Br M + 1), 434 (⁸¹Br M + 1) Gen- 5-y

(6-Bromo-2-ethyl- imidazo[1,2-a]pyridin- 3-yl)-[4-(4-chloro-phenyl)-thiazol-2-yl]- methyl-amine Gen-4-b E1 446 (⁷⁹Br ³⁵Cl), 448(⁸¹Br ³⁵Cl, ⁷⁹Br ³⁷Cl), 450 (⁸¹Br ³⁷Cl) 447 (⁷⁹Br ³⁵Cl M + 1), 449 (⁸¹Br³⁵Cl, ⁷⁹Br ³⁷Cl M + 1), 451 (⁸¹Br ³⁷Cl M + 1) Gen- 5-z

(2-Ethyl-6-nitro- imidazo[1,2-a]pyridin- 3-yl)-[4-(4-fluoro-phenyl)-thiazol-2-yl]- methyl-amine Gen-4-i E1 397 398 (M + 1) Gen- 5-aa

2-Ethyl-3-{[4-(4-fluoro- phenyl)-thiazol-2-yl]- methyl-amino}-imidazo[1,2-a]pyridine- 6-carboxylic acid methyl ester Gen-4-j E1 410411 (M + 1) Gen- 5-ab

1-(6-Bromo-3-{[4-(4- fluoro-phenyl)-thiazol- 2-yl]-methyl-amino}-imidazo[1,2-a]pyridin- 2-yl)-2-phenyl-ethane- 1,2-diol Gen-5-p see Cpd174 538 (⁷⁹Br), 540 (⁸¹Br) 539 (⁷⁹Br M + 1), 541 (⁸¹Br M + 1) Gen- 5-ac

3-(6-Bromo-3-{[4-(4- fluoro-phenyl)-thiazol- 2-yl]-methyl-amino}-imidazo[1,2-a]pyridin- 2-yl)-acrylonitrile Gen-5-q see Cpd 174 453(⁷⁹Br), 455 (⁸¹Br) 454 (⁷⁹Br M + 1), 456 (⁸¹Br M + 1) Gen- 5-ad

3-(6-Bromo-3-{[4-(4- fluoro-phenyl)-thiazol- 2-yl]-methyl-amino}-imidazo[1,2-a]pyridin- 2-yl)-acrylic acid methyl ester Gen-5-q See Cpd176 486 (⁷⁹Br), 488 (⁸¹Br 487 (⁷⁹Br M + 1), 489 (⁸¹Br M + 1) Gen- 5-ae

(6-Bromo-2-ethyl- imidazo[1,2-a]pyridin- 3-yl)-[3-(4-fluoro- phenyl)-[1,2,4]oxadiazol-5-yl]- methyl-amine Gen-4-b E3 415 (⁷⁹Br), 417 (⁸¹Br)416 (⁷⁹Br M + 1), 418 (⁸¹Br M + 1) Gen- 5-af

2-Ethyl-N-[4-(4-fluoro- phenyl)-thiazol-2-yl]-N- methyl-imidazo[1,2-a]pyridine-3,6-diamine Gen-5-z See Cpd 229 367 368 (M + 1) Gen- 5-ag

2-Ethyl-3-{[4-(4-chloro- phenyl)-thiazol-2-yl]- methyl-amino}-imidazo[1,2-a]pyridine- 6-carboxylic acid methyl ester Gen-4-j E1 426(³⁵Cl), 428 (³⁷Cl) 427 (³⁵Cl M + 1), 429 (³⁷Cl M + 1) Gen- 6-a

6-Bromo-2-ethyl- imidazo[1,2-a]pyridin- 3-ylamine Gen-2-b D1 239 (⁷⁹Br),241 (⁸¹Br) 240 (⁷⁹Br M + 1), 242 (⁸¹Br M + 1) Gen- 6-b

6-Bromo-2-(2,2,2- trifluoro-ethyl)- imiazo[1,2-a]pyridin- 3-ylamineGen-2-f D1 293 (⁷⁹Br), 295 (⁸¹Br) 294 (⁷⁹Br M + 1), 295 (⁸¹Br M + 1)Gen- 7-a

(6-Bromo-2-ethyl- imidazo[1,2-a]pyridin- 3-yl)-[3-(4-chloro- phenyl)-[1,2,4]thiadiazol-5-yl]- amine Gen-6-a H1 433 (⁷⁹Br ³⁵Cl), 435 (⁸¹Br³⁵Cl, ⁷⁹Br ³⁷Cl), 437 (⁸¹Br ³⁷Cl) 434 (⁷⁹Br ³⁵Cl M + 1), 436 (⁸¹Br ³⁵Cl,⁷⁹Br ³⁷Cl M + 1), 438 (⁸¹Br ³⁷Cl M + 1) Gen- 7-b

[6-Bromo-2-(2,2,2- trifluoro-ethyl)- imidazo[1,2-a]pyridin-3-yl]-[4-(4-chloro- phenyl)-thiazol-2-yl]- amine Gen-6-b E1 486 (⁷⁹Br³⁵Cl), 488 (⁸¹Br ³⁵Cl, ⁷⁹Br³⁷Cl), 490 (⁸¹Br ³⁷Cl) 487 (⁷⁹Br ³⁵Cl M + 1),489 (⁸¹Br ³⁵Cl, ⁷⁹Br ³⁷Cl M + 1), 491 (⁸¹Br ³⁷Cl M + 1) Gen- 7-c

(6-Bromo-2-ethyl- imidazo[1,2-a]pyridin- 3-yl)-[3-[4-fluoro- phenyl)-[1,2,4]thiadiazol-5-yl]- amine Gen-6-a H1 417 (⁷⁹Br), 419 (⁸¹Br) 418(⁷⁹Br M + 1), 420 (⁸¹Br M + 1) Gen- 8-a

N-[2-Ethyl-6-(1- methanesulfonyl- 1,2,3,6-tetrahydro- pyridin-4-yl)-imidazo[1,2-a]pyridin- 3-yl]-N-methyl- formamide Gen-3-b F2 362 363(M + 1) Gen- 8-b

N-[2-Ethyl-6-(1- methanesulfonyl- piperidin-4-yl)-imidazo[1,2-a]pyridin- 3-yl]-N-methyl- formamide Gen-8-a F6 364 365(M + 1) Gen- 8-c

4-[2-Ethyl-3-(formyl- methyl-amino)- imidazo[1,2-a]pyridin-6-yl]-piperidine-1- carboxylic acid tert- butyl ester Gen-3-b F2-F6 386387 (M + 1) Gen- 8-d

N-[2-Ethyl-6-(1- methanesulfonyl- 1,2,3,6-tetrahydro- pyridin-4-yl)-imidazo[1,2-a]pyridin- 3-yl]-N-(d₃-methyl)- formamide Gen-3-c F2 365 366(M + 1) Gen- 8-e

N-[2-Ethyl-6-(1- methanesulfonyl- piperidin-4-yl)-imidazo[1,2-a]pyridin- 3-yl]-(d₃-methyl)- formamide Gen-8-d F6 367 368(M + 1) Gen- 8-f

4-[2-Ethyl-3-(formyl- methyl-amino)-7- methyl-imidazo[1,2-a]pyridin-6-yl]- piperidine-1-carboxylic acid tert-butyl ester Gen-3-iF3 400 401 (M + 1) Gen- 8-g

4-[2-Ethyl-3-(formyl- methyl-amino)- imidazo[1,2-a]pyridin-6-yl]-3,6-dihydro-2H- pyridine-1-carboxylic acid tert-butyl esterGen-3-b F2 384 385 (M + 1) Gen- 8-h

4-[2-Ethyl-3-(formyl- methyl-amino)- imidazo[1,2-a]pyridin-6-yl]-piperazine-1- carboxylic acid tert- butyl ester Gen-3-b F1b 387388 (M + 1) Gen- 9-a

2-Ethyl-6-(1- methanesulfonyl- 1,2,3,6-tetrahydro- pyridin-4-yl)-imidazo[1,2-a]pyridin- 3-yl]-methyl-amine Gen-4-b F2 334 335 (M + 1)Gen- 9-b

[2-Ethyl-6-(1- methanesulfonyl- piperidin-4-yl)- imidazo[1,2-a]pyridin-3-yl]-methyl-amine Gen-8-b D1 336 337 (M + 1) Gen- 9-c

4-(2-Ethyl-3- methylamino- imidazo[1,2-a]pyridin- 6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butylester Gen-4-b F2 or Gen-8-g D2 356357 (M + 1) Gen- 9-d

4-(2-Ethyl-3- methylamino- imidazo[1,2-a]pyridin- 6-yl)-piperidine-1-carboxylic acid tert- butyl ester Gen-8-c D1-F7 358 359 (M + 1) Gen- 9-e

4-(2-Ethyl-3- methylamino- imidazo[1,2-a]pyridin- 6-yl)-piperazine-1-carboxylic acid tert- butyl ester Gen-8-h D1-F7 359 360 (M + 1) Gen- 9-f

[2-Ethyl-6-(1- methanesulfonyl- piperidin-4-yl)- imidazo[1,2-a]pyridin-3-yl]-(d₃-methyl)-amine Gen-8-e D1 339 340 (M + 1) Gen- 9-g

4-(2-Ethyl-7-methyl-3- (d₃-methyl)amino- imidazo[1,2-a]pyridin-6-yl)-piperidine-1- carboxylic acid tert- butyl ester Gen-8-f D1-F7 372373 (M + 1) Cpd 183 or Gen- 10-a

1-(3-{[4-(4-Chloro- phenyl)-thiazol-2-yl]- methyl-amino}-2-ethyl-imidazo[1,2-a]pyridin- 6-yl)-imidazolidin-2-one Gen-5-i F4 452 (³⁵Cl),454 (³⁷Cl) 453 (³⁵Cl M + 1) 455 (³⁷Cl M + 1) Gen- 10-b

[2-Ethyl-6-(1,2,3,6- tetrahydro-pyridin-4-yl)- imidazo[1,2-a]pyridin-3-yl]-[4-(4-fluoro- phenyl)-thiazol-2-yl]- methyl-amine Gen-5-b F2-F5b433 434 (M + 1) Cpd 216 or Gen- 10c

(2-Ethyl-6-piperidin-4- yl-imidazo[1,2- a]pyridin-3-yl)-[4-(4-fluoro-phenyl)-thiazol- 2-yl]-methyl-amine Gen-5-b F2-F6- F5b or Gen-9-cE1-F6- F5b 435 436 (M + 1) Gen- 10-d

1-(2-Ethyl-3-{[4-(4- fluoro-phenyl)-thiazol- 2-yl]-methyl-amino}-imidazo[1,2-a]pyridin- 6-yl)-piperazin-2-one Gen-5-b F4-F5b 450 451(M + 1) Gen- 10-e

(2-Ethyl-6-piperazin-1- yl-imidazo[1,2- a]pyridin-3-yl)-[4-(4-fluoro-phenyl)-thiazol- 2-yl]-methyl-amine Gen-5-b F1b-F5b or F1a 436437 (M + 1) Gen- 10-f

2-{2-[(2-Ethyl-6- piperazin-4-yl- imidazo[1,2-a]pyridin-3-yl)-methyl-amino]-5- methyl-thiazol-4-yl}-5- fluoro-benzonitrileGen-9-d E1-F5b 474 475 (M + 1) Cpd 231 or Gen- 10-g

[4-(4-Chloro-phenyl)- thiazol-2-yl]-[6-(3,6- dihydro-2H-thiopyran-4-yl)-2-ethyl- imidazo[1,2-a]pyridin- 3-yl]-methyl-amine Gen-5-i F2 466(³⁵Cl), 468 (³⁷Cl) 467 (³⁵Cl M + 1) 469 (³⁷Cl M + 1) Gen- 10-h

2-{2-[(2-Ethyl-6- piperidin-4-yl- imidazo[1,2-a]pyridin-3-yl)-methyl-amino]- thiazol-4-yl}-5-fluoro- benzonitrile Gen-9-d E1-F5b460 461 (M + 1) Gen- 10-i

2-{2-[(2-Ethyl-6- piperazin-1-yl- imidazo[1,2-a]pyridin-3-yl)-methyl-amino]- thiazol-4-yl}-5-fluoro- benzonitrile Gen-5-e F1a461 462 (M + 1) Gen- 10-j

[4-(4-Chloro-phenyl)- thiazol-2-yl]-[6-(2,5- dihydro-1H-pyrrol-3-yl)-2-ethyl-imidazo[1,2- a]pyridin-3-yl]-methyl- amine Gen-5-i F2-F5a435 (³⁵Cl), 437 (³⁷Cl) 436 (³⁵Cl M + 1), 438 (³⁷C M + 1) Gen- 10-k

2-[(2-Ethyl-6-piperazin- 1-yl-imidazo[1,2- a]pyridin-3-yl)-methyl-amino]-4-(4-fluoro- phenyl)-thiazole-5- carbonitrile Gen-5-s F1a 461 462(M + 1) Gen- 10-l

(2-Ethyl-8-fluoro-6- piperazin-1-yl- imidazo[1,2-a]pyridin-3-yl)-[4-(4-fluoro- phenyl)-thiazol-2-yl]- methyl-amine Gen-5-a F1a 454N.A. Gen- 10-m

2-[(2-Ethyl-8-fluoro-6- piperazin-1-yl- imidazo[1,2-a]pyridin-3-yl)-methyl-amino]-4- (4-fluoro-phenyl)- thiazole-5-carbonitrileGen-5-r F1a 479 480 (M + 1) Gen- 10-n

(2-Ethyl-8-methyl-6- piperazin-1-yl- imidazo[1,2-a]pyridin-3-yl)-[4-(4-fluoro- phenyl)-thiazol-2-yl]- methyl-amine Gen-5-d F1a 450451 (M + 1) Gen- 10-o

2-[(2-Ethyl-8-methyl-6- piperidin-4-yl- imidazo[1,2-a]pyridin-3-yl)-methyl-amino]-4- (4-fluoro-phenyl)- thiazole-5-carbonitrileGen-5-t F3-F5b 474 475 (M + 1) Gen- 10-p

2-{3-[4-(2-Ethyl-3-{[4- (4-fluoro-phenyl)- thiazol-2-yl]-methyl-amino}-imidazo[1,2- a]pyridin-6-yl)- piperidine-1-sulfonyl]-propyl}-isoindole-1,3- dione Gen-10-c F11- F12a 686 687 (M + 1) Gen-10-q

(2-Ethyl-7-fluoro-6- piperazin-1-yl- imidazo[1,2-a]pyridin-3-yl)-[4-(4-fluoro- phenyl)-thiazol-2-yl]- methyl-amine Gen-5-o F1a 454455 (M + 1) Gen- 10-r

2-[(2-Ethyl-7-fluoro-6- piperazin-1-yl- imidazo[1,2-a]pyridin-3-yl)-methyl-amino]-4- (4-fluoro-phenyl)- thiazole-5-carbonitrileGen-5-u F1a 479 480 (M + 1) Gen- 10-s

(2-Ethyl-7-methyl-6- piperidin-4-yl- imidazo[1,2-a]pyridin-3-yl)-[4-(4-fluoro- phenyl)-thiazol-2-yl]- methyl-amine Gen-9-g E1-F5b449 450 (M + 1) Gen- 10-t

2-{5-[(2-Ethyl-6- piperidin-4-yl- imidazo[1,2-a]pyridin-3-yl)-methyl-amino]- [1,2,4]thiadiazol-3-yl}- 5-fluoro-benzonitrileGen-9-d E5-F5b 461 462 (M + 1) Gen- 10-u

3-(4-Chloro-phenyl)- [1,2,4]thiadiazol-5-yl]- (2-ethyl-6-piperazin-1-yl-imidazo[1,2- a]pyridin-3-yl)-methyl- amine Gen-5-w F1b-F5b 453(³⁵Cl), 455 (³⁷Cl) 454 (³⁵Cl M + 1), 456 (³⁷C M + 1) Gen- 10-v

[2-Ethyl-6-(1,2,3,6- tetrahydro-pyridin-4-yl)- imidazo[1,2-a]pyridin-3-yl]-[3-(4-fluoro- phenyl)- [1,2,4]thiadiazol-5-yl]- methyl-amineGen-9-c E4-F5b or Gen-5-x F2-F5b 434 435 (M + 1) Gen- 10-w

(2-Ethyl-6-piperidin-4- yl-imidazo[1,2- a]pyridin-3-yl)-[3-(4-fluoro-phenyl)- [1,2,4]thiadiazol-5-yl]- methyl-amine Gen-10- v F6 436437 (M + 1) Gen- 10-x

2-{[6-(3,3-Dimethyl- piperazin-1-yl)-2-ethyl- 8-methyl-imidazo[1,2-a]pyridin-3-yl]-methyl- amino}-4-(4-fluoro- phenyl)-thiazole-5-carbonitrile Gen-5-t F1a 503 504 (M + 1) Gen- 10-y

[6-(1-Ethenesulfonyl- piperidin-4-yl)-2-ethyl- imidazo[1,2-a]pyridin-3-yl]-[4-(4-fluoro- phenyl)-thiazol-2-yl]- methyl-amine Gen-10-c F11 525526 (M + 1) Gen- 10-z

(2-Cyclopropyl-6- piperidin-4-yl- imidazo[1,2-a]pyridin-3-yl)-[4-(4-fluoro- phenyl)-thiazol-2-yl]- methyl-amine Gen-5-n F2-F6-F5b 447 448 (M + 1) Gen- 10-aa

3-(3-{[4-(4-Fluoro- phenyl)-thiazol-2-yl]- methyl-amino}-6-piperidin-4-yl- imidazo[1,2-a]pyridin- 2-yl)-propionitrile Gen-5-acF2-F6- F5b See Cpd 174 460 461 (M + 1) Gen- 10-ab

4-(2-Ethyl-3-{[4-(4- fluoro-phenyl)-thiazol- 2-yl]-methyl-amino}-imidazo[1,2-a]pyridin- 6-yl)-piperidin-3-ol Cpd 78 F5b 451 N.A. Gen-10-ac

[2-Ethyl-6-(1,2,3,6- tetrahydro-pyridin-4-yl)- imidazo[1,2-a]pyridin-3-yl]-[4-(4-methoxy- phenyl)-thiazol-2-yl]- methyl-amine Gen-5-f F2-F5b445 446 (M + 1) Gen- 10-ad

[4-(4-Chloro-phenyl)- thiazol-2-yl]-methyl-[6- (1,2,3,6-tetrahydro-pyridin-4-yl)-2-(2,2,2- trifluoro-ethyl)- imidazo[1,2-a]pyridin-3-yl]-amine Gen-5-v F2-F5a 503 (³⁵Cl), 505 (³⁷Cl) 504 (³⁵Cl M + 1), 506(³⁷Cl M + 1). Gen- 10-ae

[4-(4-Chloro-phenyl)- thiazol-2-yl]-[2-ethyl-6- (1,4,5,6-tetrahydro-pyridin-3-yl)- imidazo[1,2-a]pyridin- 3-yl]-methyl-amine Gen-5-i F2-F5a449 (³⁵Cl), 451 (³⁷Cl) N.A. Gen- 10-af

(2-Cyclopropyl-6- piperazin-1-yl- imidazo[1,2-a]pyridin-3-yl)-[4-(4-fluoro- phenyl)-thiazol-2-yl]- methyl-amine Gen-5-n- F1b-F5a448 449 (M + 1) Gen- 10-ag

4-(2-Ethyl-3-{[4-(4- fluoro-phenyl)-5- methoxycarbonyl-thiazol-2-yl]-methyl- amino}-imidazo[1,2- a]pyridin-6-yl)-piperazine-1-carboxylic acid tert-butyl ester Gen-9-e E1 594 595 (M + 1)Gen- 10-ah

[2-Ethyl-6-(1,2,3,6- tetrahydro-pyridin-4-yl)- imidazo[1,2-a]pyridin-3-yl]-methyl-[4-(4- trifluoromethoxy- phenyl)-thiazol-2-yl]- amineGen-5-j- F2-F5b 499 500 (M + 1) Gen- 10-ai

[2-Ethyl-6-(1,2,3,6- tetrahydro-pyridin-4-yl)- imidazo[1,2-a]pyridin-3-yl]-methyl-[4-(4- trifluoromethyl-phenyl)- thiazol-2-yl]-amine Gen-5-kF2-F5b 483 N.A. Gen- 10-aj

[4-(3,4-Difluoro- phenyl)-thiazol-2-yl]-[2- ethyl-6-[1,2,3,6-tetrahydro-pyridin-4-yl)- imidazo[1,2-a]pyridin- 3-yl]-methyl-amineGen-5-l F2-F5b 451 452 (M + 1) Gen- 10-ak

[4-(4-Chloro-phenyl)- thiazol-2-yl]-[2-ethyl-6- (1,2,3,6-tetrahydro-pyridin-4-yl)- imidazo[1,2-a]pyridin- 3-yl]-methyl-amine Gen-5-i F2-F5b449 (³⁵Cl), 451 (³⁷Cl) 450 (³⁵Cl M + 1), 452 (³⁷Cl M + 1) Gen- 10-al

[4-(2-Bromo-4-fluoro- phenyl)-thiazol-2-yl]-[2- ethyl-6-(1-methanesulfonyl- piperidin-4-yl)- imidazo[1,2-a]pyridin-3-yl]-methyl-amine Gen-9-b E1 591 (⁷⁹Br) 593 (⁸¹Br) 592 (⁷⁹Br M + 1),594 (⁸¹Br M + 1) Gen- 10-am

4-(2-(2-Carbamoyl- ethyl)-3-{[4-(4-fluoro- phenyl)-thiazol-2-yl]-methyl-amino}- imidazo[1,2-a]pyridin- 6-yl)-piperidine-1- carboxylicacid tert- butyl ester Gen-5-ad F2-F6- F13 see Cpd 176 578 579 (M + 1)Gen- 10-an

[4-(2-Ethyl-3-{[4-(4- fluoro-phenyl)-thiazol- 2-yl]-methyl-amino}-imidazo[1,2-a]pyridin- 6-yl)-piperazin-1-yl]- oxo-acetic acid Gen-10-eF9b-F13 508 509 (M + 1) Gen- 10-ao

3-Chloro-propane-1- sulfonic acid (2-ethyl-3- {[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl- amino}-imidazo[1,2- a]pyridin-6-yl)-amide Gen-5-afF11 507 (³⁵Cl), 509 (³⁷Cl); 508 (³⁵Cl M + 1), 510 (³⁷Cl M + 1) Gen-10-ap

[6-(1,4-Dioxa-8-aza- spiro[4.5]dec-8-yl)-2- ethyl-imidazo[1,2-a]pyridin-3-yl]-[4-(4- fluoro-phenyl)-thiazol- 2-yl]-methyl-amineGen-5-c F1b 493 494 (M + 1) Gen- 10-aq

1-(2-Ethyl-3-{[4-(4- fluoro-phenyl)-thiazol- 2-yl]-methyl-amino}-imidazo[1,2-a]pyridin- 6-yl)-piperidin-4-one Gen-10- ap See Cpd 211 449450 (M + 1) Gen- 10-ar

4-(2-Ethyl-3-{[4-(4- fluoro-phenyl)-5- methoxycarbonyl-thiazol-2-yl]-methyl- amino}-imidazo[1,2- a]pyridin-6-yl)-piperidine-1-carboxylic acid tert-butyl ester Gen-9-d E1 593 594 (M + 1)Cpd 1

2-[(2-Ethyl-8-methyl-6- piperazin-1-yl- imidazo[1,2-a]pyridin-3-yl)-methyl-amino]-4- (4-fluoro-phenyl)- thiazole-5-carbonitrileGen-5-t F1b-F5b 475 476 (M + 1) Cpd 78

4-(2-Ethyl-3-{[4-(4- fluoro-phenyl)-thiazol- 2-yl]-methyl-amino}-imidazo[1,2-a]pyridin- 6-yl)-3-hydroxy- piperidine-1-carboxylic acidtert-butyl ester Gen-5-c F2-see Cpd 78 551 552 (M + 1) Cpd 161

2-{2-[(2-Ethyl-6- piperazin-1-yl- imidazo[1,2-a]pyridin-3-yl)-methyl-amino]-5- methyl-thiazol-4-yl}-5- fluoro-benzonitrileGen-5-m F1a 475 476 (M + 1) Cpd 177

[6-(3-Amino-azetidin-1- yl)-2-ethyl-imidazo[1,2- a]pyridin-3-yl]-[4-(4-fluoro-phenyl)-thiazol- 2-yl]-methyl-amine Gen-5-b F1b-F5a 422 423(M + 1) Gen- 11-a

2-(2-Bromo-acetyl)-5- fluoro-benzonitrile G1 241 (⁷⁹Br), 243 (⁸¹Br) 242(⁷⁹Br M + 1), 244 (⁸¹Br M + 1) Gen- 11-b

2-Bromo-1-(2-bromo-4- fluoro-phenyl)-ethanone G1 294 (⁷⁹Br, ⁷⁹Br) 296(⁷⁹Br, ⁸¹Br) 298 (⁸¹Br, ⁸¹Br) N.A. Gen- 11-c

2-(2-Bromo-propionyl)- 5-fluoro- benzonitrile G1 255 (⁷⁹Br), 257 (⁸¹Br)N.A. Gen- 11-d

2-Bromo-1-(4-fluoro- phenyl)-(d₂-ethanone) see example Gen-11- d 218(⁷⁹Br), 220 (⁸¹Br) N.A. Gen- 12-a

2-Chloro-4-(4-fluoro- phenyl)-thiazole-5- carbonitrile G2 238 (³⁵Cl),240 (³⁷Cl) 239 (³⁵Cl M + 1), 241 (³⁷Cl M + 1) Gen- 13-a

2-Chloro-1-(3-hydroxy- azetidin-1-yl)-ethanone G3a 149 (³⁵Cl), 151(³⁷Cl) N.A Gen- 13-b

2-Chloro-1-(3-hydroxy- 3-methyl-azetidin-1-yl)- ethanone G3a 163 (³⁵Cl),165 (³⁷Cl) 164 (³⁵Cl M + 1) 166 (³⁷Cl M + 1) Gen- 13-c

2-Chloro-1-(3- hydroxymethyl-azetidin- 1-yl)-ethanone G3b 163 (³⁵Cl),165 (³⁷Cl) 164 (³⁵Cl M + 1) 166 (³⁷Cl M + 1) Gen- 13-d

2-Chloro-1-(3-fluoro- azetidin-1-yl)-ethanone G3a 151 (³⁵Cl), 153 (³⁷Cl)N.A Gen- 13-e

2-Chloro-1-(3,3- difluoro-azetidin-1-yl)- ethanone G3a 169 (³⁵Cl), 171(³⁷Cl) 170 (³⁵Cl M + 1) 172 (³⁷Cl M + 1) Gen- 13-f

1-Azetidin-1-yl-2- chloro-ethanone G3a 133 (³⁵Cl), 135 (³⁷Cl) N.A. Gen-13-g

(S)-2-Chloro-1-(3- hydroxy-pyrrolidin-1- yl)-ethanone G3a 163 (³⁵Cl),165 (³⁷Cl) 164 (³⁵Cl M + 1) 166 (³⁷Cl M + 1) Gen- 13-h

(R)-2-Chloro-1-(3- hydroxy-pyrrolidin-1- yl)-ethanone G3b 163 (³⁵Cl),165 (³⁷Cl) 164 (³⁵Cl M + 1) 166 (³⁷Cl M + 1) Gen- 13-i

(S)-1-(2-Chloro-acetyl)- pyrrolidine-3- carbonitrile G3b 172 (³⁵Cl), 174(³⁷Cl) 173 (³⁵Cl M + 1), 175 (³⁷Cl M + 1) Gen- 13-j

N-[1-(2-Chloro-acetyl)- pyrrolidin-3-yl]- acetamide see Gen- 13-j 204(³⁵Cl), 206 (³⁷Cl) N.A. Gen- 13-k

2-Chloro-1-(3- hydroxymethyl- pyrrolidin-1-yl)- ethanone G3b 177 (³⁷Cl),179 (³⁷Cl) N.A. Gen- 13-l

2-Chloro-1-morpholin- 4-yl-ethanone G3b 163 (³⁵Cl), 165 (³⁷Cl) N.A. Gen-13-m

2-Chloro-N- cyclopropyl-acetamide G3b 133 (³⁵Cl), 135 (³⁷Cl) 134 (³⁵ClM + 1), 136 (³⁷Cl M + 1) Gen- 13-n

2-Chloro-N-(2-hydroxy- ethyl)-N-methyl- acetamide G3b 151 (³⁵Cl), 153(³⁷Cl) N.A. Gen- 13-o

2-Chloro-N-methoxy-N- methyl-acetamide G3b 137 (³⁵Cl), 139 (³⁷Cl) 138(³⁵Cl M + 1) 140 (³⁷Cl M + 1) Gen- 13-p

2-Chloro-N- cyanomethyl-N-methyl- acetamide G3b 146 (³⁵Cl), 148 (³⁷Cl)N.A. Gen- 13-q

2-Chloro-N-(3-hydroxy- propyl)-acetamide G3b 151 (³⁵Cl), 153 (³⁷C) N.A.

TABLE II NMR data of the Intermediates used towards the compounds of theinvention. Int NMR data (δ) Gen- ¹H NMR (400 MHz, CDCl₃) δ ppm, presenceof 2 rotamers 8.71 (0.5 H, bs), 8.56 (0.5 H, 2-k s), 8.52 (0.5 H, bs),8.16 (0.5 H, d), 8.04 (0.5 H, bs), 7.77 (0.5 H, dd), 7.71 (0.5 H, dd),7.67 (0.5 H, bs), 7.53 (0.5 H, d), 7.49 (0.5 H, d), 3.95 (1.5 H, s),3.92 (1.5 H, s), 2.79 (1 H, q), 2.72 (1 H, q), 1.36-1.26 (3 H, m) Gen-¹H NMR (400 MHz, CDCl₃) δ ppm 8.22 (1 H, s), 7.94 (1 H, s), 7.50 (1 H,d), 7.34 (1 H, 3-c d), 2.75 (2H, q), 1.34 (3 H, t) Gen- ¹H NMR (300 MHz,CDCl₃) δ ppm 7.56 (1 H, dd), 7.41 (1 H, dd), 7.20-7.08 (1 H, m), 11-b4.48 (2 H, s) Gen- ¹H NMR (400 MHz, CDCl₃) δ ppm 8.03 (1 H, dd), 7.55 (1H, dd), 7.46-7.38 (1 H, m), 11-c 5.26 (1 H, q), 1.96 (3 H, d) Gen- ¹HNMR (400 MHz, CDCl₃) δ ppm 8.01-7.96 (2 H, m), 7.17-7.08 (2 H, m) 11-dGen- ¹H NMR (400 MHz, CDCl₃) δ ppm 4.78-4.68 (1 H, m), 4.56-4.47 (1 H,m), 13-a 4.38-4.29 (1 H, m), 4.16 (1 H, ddd), 3.97 (1 H, dd), 3.91 (2 H,s), 2.56 (1 H, d) Gen- ¹H NMR (300 MHz, CDCl₃) δ ppm 5.49-5.40 (0.5 H,m), 5.32-5.20 (0.5 H, m), 13-d 4.69-4.50 (1 H, m), 4.49-4.29 (2 H, m),4.28-4.10 (1 H, m), 3.93 (2 H, s) Gen- ¹H NMR (300 MHz, CDCl₃) δ ppm4.18 (2 H, t), 3.96 (2 H, t), 3.73 (2 H, s), 2.27-2.14 (2 13-f H, m)Gen- ¹H NMR (400 MHz, CDCl₃) δ ppm 5.33-5.01 (2 H, m), 4.60-4.41 (1 H,m), 13-j 3.79-3.65 (2 H, m), 3.63-3.44 (2 H, m), 1.97 (3 H, d),1.90-1.80 (2 H, m)

TABLE III Illustrative compounds of the invention. Mtd MS Cpd StructuresName (Int) MW Ms'd  1

2-((2-ethyl-8-methyl-6- (piperazin-1- yl)imidazo[1,2- a]pyridin-3-yl)(methyl)amino)-4-(4- fluorophenyl)thiazole-5- carbonitrile F1b- F5b(Gen- 5-t) 475 476 (M + 1)  2

2-((2-ethyl-6-(4-(2-(3- hydroxyazetidin-1-yl)-2- oxoethyl)piperazin-1-yl)-8- methylimidazo[1,2- a]pyridin-3- yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5- carbonitrile F8 (Cpd 1) 588 589 (M + 1)  3

2-((2-ethyl-6-(4-(2-(3- hydroxy-3- methylazetidin-1-yl)-2-oxoethyl)piperazin-1- yl)-8- methylimidazo[1,2- a]pyridin-3-yl)(methyl)amino)-4-(4- fluorophenyl)thiazole-5- carbonitrile F8 (Cpd 1)602 603 (M + 1)  4

(R)-2-((2-ethyl-6-(4-(2- (3-hydroxypyrrolidin-1- yl)-2-oxoethyl)piperazin-1- yl)-8- methylimidazo[1,2- a]pyridin-3-yl)(methyl)amino)-4-(4- fluorophenyl)thiazole-5- carbonitrile F8 (Cpd 1)602 603 (M + 1)  5

(S)-2-((2-ethyl-6-(4-(2- (3-hydroxypyrrolidin-1- yl)-2-oxoethyl)piperazin-1- yl)-8- methylimidazo[1,2- a]pyridin-3-yl)(methyl)amino)-4-(4- fluorophenyl)thiazole-5- carbonitrile B1/B2- C1-D1- E2- F1b- F5b- F8 (Cpd 1) 602 603 (M + 1)  6

2-((2-ethyl-6-(4-(2-(3- hydroxyazetidin-1-yl)-2- oxoethyl)-3,3-dimethylpiperazin-1-yl)- 8-methylimidazo[1,2- a]pyridin-3-yl)(methyl)amino)-4-(4- fluorophenyl)thiazole-5- carbonitrile F8 (Gen-10-x) 616 617 (M + 1)  7

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)-8-methylimidazo[1,2- a]pyridin-6- yl)piperazin-1-yl)-1-(3-hydroxyazetidin-1- yl)ethanone F8 (Gen- 10n) 563 564 (M + 1)  8

(R)-2-(4-(2-ethyl-3-((4- (4-fluorophenyl)thiazol- 2-yl)(methyl)amino)-8-methylimidazo[1,2- a]pyridin-6- yl)piperazin-1-yl)-1-(3-hydroxypyrrolidin-1- yl)ethanone F8 (Gen- 10n) 577 578 (M + 1)  9

(S)-2-(4-(2-ethyl-3-((4- (4-fluorophenyl)thiazol- 2-yl)(methyl)amino)-8-methylimidazo[1,2- a]pyridin-6- yl)piperazin-1-yl)-1-(3-hydroxypyrrolidin-1- yl)ethanone F8 (Gen- 10n) 577 578 (M + 1)  10

2-((2-ethyl-6-(1-(2-(3- hydroxyazetidin-1-yl)-2- oxoethyl)piperidin-4-yl)-8- methylimidazo[1,2- a]pyridin-3- yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5- carbonitrile F8 (Gen- 10-o) 587 588 (M + 1)  11

2-(ethyl(2-ethyl-8- methyl-6-(1- (methylsulfonyl)- 1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2- a]pyridin-3-yl)amino)-4- (4-fluorophenyl)thiazole-5- carbonitrile F2 (Gen- 5-h) 564 565 (M + 1)  12

2-((2-ethyl-8-fluoro-6- (4-(2-(3- hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1- yl)imidazo[1,2- a]pyridin-3-yl)(methyl)amino)-4-(4- fluorophenyl)thiazole-5- carbonitrile F8 (Gen-10-m) 592 593 (M + 1)  13

2-(4-(3-((5-cyano-4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)-2-ethyl-8- fluoroimidazo[1,2- a]pyridin-6- yl)piperazin-1-yl)-N-methylacetamide F8 (Gen- 10-m) 550 551 (M + 1)  14

2-(4-(2-ethyl-8-fluoro-3- ((4-(4- fluorophenyl)thiazol-2-yl)(methyl)amino) imidazo[1,2-a]pyridin-6- yl)piperazin-1-yl)-1-(3-hydroxyazetidin-1- yl)ethanone F8 (Gen- 10-l) 567 568 (M + 1)  15

(S)-2-(4-(2-ethyl-8- fluoro-3-((4-(4- fluorophenyl)thiazol-2-yl)(methyl)amino) imidazo[1,2-a]pyridin-6- yl)piperazin-1-yl)-1-(3-hydroxypyrrolidin-1- yl)ethanone F8 (Gen- 10-l) 581 582 (M + 1)  16

(R)-2-(4-(2-ethyl-8- fluoro-3-((4-(4- fluorophenyl)thiazol-2-yl)(methyl)amino) imidazo[1,2-a]pyridin-6- yl)piperazin-1-yl)-1-(3-hydroxypyrrolidin-1- yl)ethanone F8 (Gen- 10-1) 581 582 (M + 1)  17

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)-7-methylimidazo[1,2- a]pyridin-6-yl)piperidin- 1-yl)-1-(3-hydroxyazetidin-1- yl)ethanone F8 (Gen- 10-s) 562 563 (M + 1)  18

2-[(2-Ethyl-7-fluoro-6- {4-[2-(3-hydroxy- azetidin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}- imidazo[1,2-a]pyridin-3- yl)-methyl-amino]-4-(4-fluoro-phenyl)-thiazole- 5-carbonitrile F8 (Gen- 10-r) 592 593 (M + 1) 19

2-[4-(2-Ethyl-7-fluoro- 3-{[4-(4-fluoro-phenyl)- thiazol-2-yl]-methyl-amino}-imidazo[1,2- a]pyridin-6-yl)- piperazin-1-yl]-1-(3-hydroxy-azetidin-1-yl)- ethanone F8 (Gen- 10-q) 567 568 (M + 1)  20

(R)-2-[4-(2-Ethyl-7- fluoro-3-{[4-(4-fluoro- phenyl)-thiazol-2-yl]-methyl-amino}- imidazo[1,2-a]pyridin-6- yl)-piperazin-1-yl]-1-(3-hydroxy-pyrrolidin-1- yl)-ethanone A-B1- C1- D2- E1- F1a- F8 (Gen- 10-q)581 594 (M + Na)  21

(S)-2-[4-(2-Ethyl-7- fluoro-3-{[4-(4-fluoro- phenyl)-thiazol-2-yl]-methyl-amino}- imidazo[1,2-a]pyridin-6- yl)-piperazin-1-yl]-1-(3-hydroxy-pyrrolidin-1- yl)-ethanone F8 (Gen- 10-q) 581 594 (M + Na)  22

2-(4-(3-((5-cyano-4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)-2-ethylimidazo[1,2- a]pyridin-6- yl)piperazin-1-yl)-N- methylacetamide F8(Gen- 10-k) 587 588 (M + 1)  23

tert-butyl 4-(2-ethyl-3- ((4-(4- fluorophenyl)thiazol-2-yl)(methyl)amino) imidazo[1,2-a]pyridin-6- yl)piperazine-1- carboxylateF1b (Gen- 5-c) 536 537 (M + 1)  24

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperazin-1-yl)-1-(3- hydroxyazetidin-1-yl)ethanone F8 (Gen- 10-e) 549 550 (M + 1)  25

(S)-2-(4-(2-ethyl-3-((4- (4-fluorophenyl)thiazol- 2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperazin-1-yl)-1-(3- hydroxypyrrolidin-1-yl)ethanone F8 (Gen- 10-e) 563 564 (M + 1)  26

(R)-2-(4-(2-ethyl-3-((4- (4-fluorophenyl)thiazol- 2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperazin-1-yl)-1-(3- hydroxypyrrolidin-1-yl)ethanone F8 (Gen- 10-e) 563 564 (M + 1)  27

N-(1-(2-(4-(2-ethyl-3- ((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperazin-1- yl)acetoyl)pyrrolidin-3-yl)acetamide F8 (Gen- 10-e) 604 605 (M + 1)  28

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperazin-1-yl)-1-(3- fluoroazetidin-1-yl)ethanone F8 (Gen- 10-e) 551 552 (M + 1)  29

1-(3,3-difluoroazetidin- 1-yl)-2-(4-(2-ethyl-3- ((4-(4-fluorophenyl)thiazol-2- yl)(methyl)amino)- imidazo[1,2-a]pyridin-6-yl)piperazin-1- yl)ethanone F8 (Gen- 10-e) 569 570 (M + 1)  30

1-(azetidin-1-yl)-2-(4- (2-ethyl-3-((4-(4- fluorophenyl)thiazol-2-yl)(methyl)amino) imidazo[1,2-a]pyridin-6 yl)piperazin-1- yl)ethanone F8(Gen- 10-e) 533 534 (M + 1)  31

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperazin-1-yl)-1- (pyrrolidin-1-yl)ethanone F8 (Gen- 10-e) 547 548 (M + 1)  32

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperazin-1-yl)-1- morpholinoethanone F8(Gen- 10-e) 563 564 (M + 1)  33

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperazin-1- yl)acetamide F8 (Gen- 10-e) 493494 (M + 1)  34

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperazin-1-yl)-1-(3-(hydroxymethyl)azetidin- 1-yl)ethanone F8 (Gen- 10-e) 563 564 (M + 1) 35

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperazin-1-yl)-N,N- dimethylacetamide F8(Gen- 10-e) 521 522 (M + 1)  36

ethyl 2-(4-(2-ethyl-3- ((4-(4- fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo [1,2-a]pyridin-6- yl)piperazin-1-yl)acetate F8(Gen- 10-e) 522 523 (M + 1)  37

ethyl 2-(4-(2-ethyl-3- ((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperazin-1- yl)propionoate F8 (Gen- 10-e)536 537 (M + 1)  38

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a] pyridin-6- yl)piperazin-1- yl)acetonitrile F8 (Gen- 10-e)475 476 (M + 1)  39

N-(6-(4-((1- cyclopropyl-1H- tetrazol-5- yl)methyl)piperazin-1-yl)-2-ethylimidazo[1,2- a]pyridin-3-yl)-4-(4- fluorophenyl)-N-methylthiazol-2-amine F8 (Gen- 10-e) 558 559 (M + 1)  40

N-(2-ethyl-6-(4-oxazol- 2-ylmethyl)piperazin-1- yl)imidazo[1,2-a]pyridin-3-yl)-4-(4- fluorophenyl)-N- methylthiazol-2-amine F8 (Gen-10-e) 517 518 (M + 1)  41

N-(6-(4-((1,2,4- oxadiazol-3- yl)methyl)piperazin-1-yl)-2-ethylimidazo[1,2- a]pyridin-3-yl)-4-(4- fluorophenyl)-N-methylthiazol-2-amine F8 (Gen- 10-e) 518 519 (M + 1)  42

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperazin-1-yl)acetic acid F13 (Cpd 36) 494495 (M + 1)  43

2-hydroxyethyl 4-(2- ethyl-3-((4-(4- fluorophenyl)thiazol-2-yl)(methyl)amino) imidazo[1,2-a]pyridin-6- yl)piperazine-1- carboxylatesee Cpd 43 (Gen- 10-e) 524 525 (M + 1)  44

tert-butyl 2-(4-(2-ethyl- 3-((4-(4- fluorophenyl)thiazol-2-yl)(methyl)amino) imidazo[1,2-a]pyridin-6- yl)piperazine-1-carbonyl)pyrrolidine-1- carboxylate F9a (Gen- 10-e) 633 634 (M + 1)  45

tert-butyl 3-(4-(2-ethyl- 3-((4-(4- fluorophenyl)thiazol-2-yl)(methyl)amino) imidazo[1,2-a]pyridin-6- yl)piperazine-1-carbonyl)pyrrolidine-1- carboxylate F9a (Gen- 10-e) 633 634 (M + 1)  46

(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperazin-1- yl)(pyrrolidin-2- yl)methanoneF5b (Cpd 44) 533 534 (M + 1)  47

(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperazin-1- yl)(pyrrolidin-3- yl)methanoneF5b (Cpd 45) 533 534 (M + 1)  48

1-(3-(4-(2-ethyl-3-((4- (4-fluorophenyl)thiazol- 2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperazine-1- carbonyl)pyrrolidin-1-yl)ethanone F9b (Cpd 47) 575 576 (M + 1)  49

(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperazin-1-yl)(1- (methylsulfonyl)pyrrolidin-3-yl) methanone F11 (Cpd 47) 611 612 (M + 1)  50

1-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperazin-1-yl)-2- hydroxyethanone F9a (Gen-10-e) 494 495 (M + 1)  51

1-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperazin-1- yl)propan-1-one F9b (Gen- 10-e)492 493 (M + 1)  52

1-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperazin-1-yl)-4- hydroxybutan-1-one F9b(Gen- 10-e) 522 523 (M + 1)  53

4-(dimethylamino)-1-(4- (2-ethyl-3-((4-(4- fluorophenyl)thiazol-2-yl)(methyl)amino) imidazo[1,2-a]pyridin-6- yl)piperazin-1-yl)butan-1-one F9b- F12a (Gen- 10-e) 549 550 (M + 1)  54

N-(2-ethyl-6-(4- (methylsulfonyl) piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4- fluorophenyl)-N- methylthiazol-2-amine F11(Gen- 10-e) 514 515 (M + 1)  55

N-(6-(4-(3- chloropropylsulfonyl) piperazin-1-yl)-2- ethylimidazo[1,2-a]pyridin-3-yl)-4-(4- fluorophenyl)-N- methylthiazol-2-amine F11 (Gen-10-e) 576 577 (M + 1)  56

N-(6-(4-(3- (dimethylamino)propyl- sulfonyl)piperazin-1-yl)-2-ethylimidazo[1,2-a] pyridin-3-yl)-4-(4- fluorophenyl)-N-methylthiazol-2-amine F12a (Cpd 55) 585 586 (M + 1)  57

N-(2-ethyl-6-(4-(3- (pyrrolidin-1- yl)propylsulfonyl)piperazin-1-yl)imidazo [1,2-a]pyridin-3-yl)-4- (4-fluorophenyl)-N-methylthiazol-2-amine F12a (Cpd 55) 611 612 (M + 1)  58

3-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperazin-1- ylsulfonyl)propan-1-ol F12b-F13 (Cpd 55) 558 559 (M + 1)  59

methyl 2-(4-(2-ethyl-3- ((4-(4- fluorophenyl)thiazol-2-yl)(methyl)amino) imidazo[1,2-a]pyridin-6- yl)piperazin-1-ylsulfonyl)acetate F11 (Gen- 10-e) 572 573 (M + 1)  60

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperazin-1- ylsulfonyl)acetic acid F13 (Cpd59) 558 559 (M + 1)  61

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperazin-1- ylsulfonyl)acetamide see Cpd 61(Cpd 60) 557 558 (M + 1)  62

tert-butyl 4-(2-ethyl-3- ((4-(4- fluorophenyl)thiazol-2-yl)(methyl)amino) imidazo[1,2-a]pyridin-6- yl)-3- oxopiperazine-1-carboxylate F4 (Gen- 5-b) 550 551 (M + 1)  63

tert-butyl 4-(3-((4-(4- chlorophenyl)thiazol-2- yl)(methyl)amino)-2-ethylimidazo[1,2-a] pyridin-6-yl)-3- oxopiperazine-1- carboxylate F4(Gen- 5-i) 566 (³⁵Cl), 568 (³⁷Cl) 567 (³⁵Cl M + 1)  64

ethyl 2-(4-(2-ethyl-3- ((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)-3-oxopiperazin-1- yl)acetate see Cpd 64(Gen- 10-d) 536 537 (M + 1)  65

1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin- 6-yl)-4- (methylsulfonyl) piperazin-2-one F11(Gen- 10-d) 528 529 (M + 1)  66

N-(2-ethyl-6-(1- (methylsulfonyl)- 1,2,3,6- tetrahydropyridin-4-yl)imidazo[1,2- a]pyridin-3-yl)-4-(4- fluorophenyl)-N-methylthiazol-2-amine F11 (Gen- 10-b) 511 512 (M + 1)  67

N-(6-(1- (chloromethylsulfonyl)- 1,2,3,6- tetrahydropyridin-4-yl)-2-ethylimidazo[1,2- a]pyridin-3-yl)-4-(4- fluorophenyl)-N-methylthiazol-2-amine F11 (Gen- 10-b) 545 546 (M + 1)  68

4-(4-chlorophenyl)-N- (2-ethyl-6-(1- (methylsulfonyl)-2,5-dihydro-1H-pyrrol-3- yl)imidazo[1,2- a]pyridin-3-yl)-N-methylthiazol-2-amine F11 (Gen- 10-j) 513 (³⁵Cl), 515 (³⁷Cl) 514 (³⁵ClM + 1) 516 (³⁷Cl M + 1)  69

4-(4-chlorophenyl)-N- (2-ethyl-6-(1- (methylsulfonyl)- 1,4,5,6-tetrahydropyridin-3- yl)imidazo[1,2-a] pyridin-3-yl)-N-methylthiazol-2-amine F11 (Gen- 10-ae) 527 (³⁵Cl), 529 (³⁷Cl) 528 (³⁵ClM + 1) 530 (³⁷Cl M + 1)  70

4-(4-tert-butylphenyl)- N-(2-ethyl-6-(1- (methylsulfonyl)- 1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2- a]pyridin-3-yl)-N-methylthiazol-2-amine F2 (Gen- 5-g)- 549 550 (M + 1)  71

N-(2-ethyl-6-(1- (methylsulfonyl)- 1,2,3,6- tetrahydropyridin-4-yl)imidazo[1,2- a]pyridin-3-yl)-4-(4- methoxyphenyl)-N-methylthiazol-2-amine F11 (Gen- 10-ac) 523 524 (M + 1)  72

N-(2-ethyl-6-(1- (methylsulfonyl)- 1,2,3,6- tetrahydropyridin-4-yl)imidazo[1,2- a]pyridin-3-yl)-N- methyl-4-(4- (trifluoromethoxy)phenyl)thiazol-2-amine F11 (Gen- 10-ah) 577 578 (M + 1)  73

4-(3,4-difluorophenyl)- N-(2-ethyl-6-(1- (methylsulfonyl)- 1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a] pyridin-3-yl)-N-methylthiazol-2-amine F11 (Gen- 10-aj) 529 530 (M + 1)  74

3-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)-5,6-dihydro- pyridin- 1(2H)-ylsulfonyl)propyl acetate F11- F12b (Gen- 10-b)- 597 598 (M + 1)  75

3-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)-5,6-dihydropyridin- 1(2H)-ylsulfonyl)propan-1-ol F13 (Cpd 74) 555 556 (M + 1)  76

4-(2-ethyl-3-((4-(4- chlorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)-3,6-dihydro-2H- thiopyran 1,1-dioxide seeCpd 76 (Gen- 10-g or cpd 231) 498 (³⁵Cl), 500 (³⁷Cl) 499 (³⁵Cl M + 1)501 (³⁷Cl M + 1)  77

N-(2-ethyl-6-(1- (methylsulfonyl)- 1,2,3,6- tetrahydropyridin-4-yl)imidazo[1,2- a]pyridin-3-yl)-5-fluoro- 4-(4-fluorophenyl)-N-methylthiazol-2-amine F16b (Cpd 66) 529 530 (M + 1)  78

tert-butyl 4-(2-ethyl-3- ((4-(4- fluorophenyl)thiazol-2-yl)(methyl)amino) imidazo[1,2-a]pyridin-6- yl)-3- hydroxypiperidine-1-carboxylate F2- see Cpd 78 (Gen- 5-c) 551 552 (M + 1)  79

4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)-1-(methylsulfonyl) piperidin-3-ol F11 (Gen-10-ab) 529 530 (M + 1)  80

N-(2-ethyl-6-(1- (methylsulfonyl) piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)- 4-(4-fluorophenyl)-N- methylthiazol-2-amine F11-F6 (Gen- 10-b) 513 514 (M + 1)  81

4-(4-tert-butylphenyl)- N-(2-ethyl-6-(1- (methylsulfonyl)piperidin-4-yl)imidazo [1,2-a]pyridin-3-yl)-N- methylthiazol-2-amine F2-F6 (Gen- 5-g)- 551 552 (M + 1)  82

N-(2-ethyl-6-(1- (methylsulfonyl) piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4- methoxyphenyl)-N- methylthiazol-2-amine F11-F6 (Gen- 10-ac) 525 526 (M + 1)  83

4-(3,4-difluorophenyl)- N-(2-ethyl-6-(1- (methylsulfonyl)piperidin-4-yl)imidazo [1,2-a]pyridin-3-yl)-N- methylthiazol-2-amineF11- F6 (Gen- 10-aj) 531 532 (M + 1)  84

N-(2-ethyl-6-(1- (methylsulfonyl) piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-N- methyl-4-(4- (trifluoromethyl)phenyl)thiazol-2-amine F11- F6 (Gen- 10-ai) 563 564 (M + 1)  85

N-(2-ethyl-6-(1- (methylsulfonyl) piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-N- methyl-4-(4- (trifluoromethoxy)phenyl)thiazol-2-amine F6- F11 (Gen- 10-ah) 579 580 (M + 1)  86

N-(6-(1-(3- chloropropylsulfonyl) piperidin-4-yl)-2- ethylimidazo[1,2-a]pyridin-3-yl)-4-(4- fluorophenyl)-N- methylthiazol-2-amine F11 (Gen-10-c) 575 (³⁵Cl), 577 (³⁷Cl) 576 (³⁵Cl M + 1) 578 (³⁷Cl M + 1)  87

N-(6-(1-(3- (dimethylamino)propyl- sulfonyl)piperidin-4-yl)-2-ethylimidazo[1,2- a]pyridin-3-yl)-4-(4- fluorophenyl)-N-methylthiazol-2-amine F12a (Cpd 86) 584 585 (M + 1)  88

N-(2-ethyl-6-(1-(3- morpholinopropyl- sulfonyl)piperidin-4-yl)imidazo[1,2-a] pyridin-3-yl)-4-(4- fluorophenyl)-N-methylthiazol-2-amine F12a (Cpd 86) 626 627 (M + 1)  89

N-(2-ethyl-6-(1-(3- (pyrrolidin-1- yl)propylsulfonyl)piperidin-4-yl)imidazo [1,2-a]pyridin-3-yl)-4- (4-fluorophenyl)-N-methylthiazol-2-amine F12a (Cpd 86) 610 611 (M + 1)  90

N-(6-(1-(3- aminopropylsulfonyl) piperidin-4-yl)-2- ethylimidazo[1,2-a]pyridin-3-yl)-4-(4- fluorophenyl)-N- methylthiazol-2-amine see Cpd (Gen-10-p) 556 557 (M + 1)  91

N-(2-ethyl-6-(1-(2- morpholinoethylsulfonyl) piperidin-4-yl)imidazo[1,2-a] pyridin-3-yl)-4-(4- fluorophenyl)-N-methylthiazol-2-amine see Cpd 91 (Gen- 10-y) 612 613 (M + 1)  92

4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperidine-1- sulfonamide see Cpd 92) (Gen-10-c) 514 515 (M + 1)  93

3-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin- 6-yl)piperidin-1- ylsulfonyl)propyl acetate F12b(Cpd 86) 599 600 (M + 1)  94

3-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperidin-1- ylsulfonyl)propan-1-ol F13 (Cpd93) 557 558 (M + 1)  95

3-(4-(2-ethyl-3-((5- fluoro-4-(4- fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo [1,2-a]pyridin-6- yl)piperidin-1-ylsulfonyl)propan-1-ol F16b (Cpd 94) 575 576 (M + 1)  96

2-(2-((2-ethyl-6-(1- (methylsulfonyl) piperidin-4-yl)imidazo[1,2-a]pyridin-3- yl)(methyl)amino) thiazol-4-yl)-5- fluorobenzonitrileE1 (Gen- 9-b) 538 539 (M + 1)  97

2-(2-((2-ethyl-6-(1- (methylsulfonyl) piperidin-4-yl)imidazo[1,2-a]pyridin-3- yl)(methyl)amino)-5- methylthiazol-4-yl)-5-fluorobenzonitrile E1 (Gen- 9-b) 552 553 (M + 1)  98

N-(2-ethyl-6-(1- (methylsulfonyl) piperidin-4-yl) imidazo[1,2-a]pyridin-3-yl)-4-(4- fluoro-2-methylphenyl)- N-methylthiazol-2- amine E1(Gen- 9-b) 527 528 (M + 1)  99

4-(2-chloro-4- fluorophenyl)-N-(2- ethyl-6-(1- (methylsulfonyl)piperidin-4-yl)imidazo [1,2-a]pyridin-3-yl)-N- methylthiazol-2-amine E1(Gen- 9-b) 547 (³⁵Cl) 549 (³⁷Cl) 548 (³⁵Cl M + 1) 100

4-(2,4-difluorophenyl)- N-(2-ethyl-6-(1- (methylsulfonyl)piperidin-4-yl)imidazo [1,2-a]pyridin-3-yl)-N- methylthiazol-2-amine E1(Gen- 9-b) 531 532 (M + 1) 101

N-(2-ethyl-6-(1- (methylsulfonyl) piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-4- (4-fluorophenyl)-N,5- dimethylthiazol-2-amine E1(Gen- 9-b) 527 528 (M + 1) 102

4-(4-fluorophenyl)-N- (2-ethyl-6-(1- (methylsulfonyl)piperidin-4-yl)imidazo [1,2-a]pyridin-3-yl)-N- (d₃-methyl)thiazol-2-amine E1 (Gen- 9-f) 516 517 (M + 1) 103

4-(4-fluorophenyl)-N- (2-ethyl-6-(1- (methylsulfonyl)piperidin-4-yl)imidazo [1,2-a]pyridin-3-yl)-N- (d₃-methyl)-(d-thiazol-2)-amine B1-C1- F2- F6- D1- E1 (Gen- 9-f) 517 518 (M + 1) 104

methyl 2-((2-ethyl-6-(1- (methylsulfonyl) piperidin-4-yl)imidazo[1,2-a]pyridin-3- yl)(methyl)amino)-4-(4- fluorophenyl)thiazole-5-carboxylate E1 (Gen- 9-b) 571 572 (M + 1) 105

1-(2-((2-ethyl-6-(1- (methylsulfonyl) piperidin-4-yl)imidazo[1,2-a]pyridin-3- yl)(methyl)amino)-4-(4- fluorophenyl)thiazol-5-yl)ethanone see Cpd 105 (Cpd 104) 555 556 (M + 1) 106

N-(2-(2-((2-ethyl-6-(1- (methylsulfonyl) piperidin-4-yl)imidazo[1,2-a]pyridin-3- yl)(methyl)amino) thiazol-4-yl)-5-fluorophenyl)acetamide see Cpd 106 (Gen- 10-al) 570 571 (M + 1) 107

(2-(2-((2-ethyl-6-(1- (methylsulfonyl) piperidin-4-yl)imidazo[1,2-a]pyridin-3- yl)(methyl)amino) thiazol-4-yl)-5-fluorophenyl)methanol see cpd 107 (Gen- 10-al) 543 544 (M + 1) 108

ethyl 2-(4-(2-ethyl-3- ((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)-5,6-dihydropyridin- 1(2H)-yl)acetate F8(Gen- 10-b)- 519 520 (M + 1) 109

ethyl 2-(4-(2-ethyl-3- ((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperidin-1-yl)acetate F8 (Gen- 10-c) 521522 (M + 1) 110

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperidin-1-yl)-(3- hydroxyazetidin-1-yl)ethanone F8 (Gen- 10-c) 548 549 (M + 1) 111

(R)-2-(4-(2-ethyl-3-((4- (4-fluorophenyl)thiazol- 2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperidin-1-yl)-1-(3- hydroxypyrrolidin-1-yl)ethanone F8 (Gen- 10-c) 562 563 (M + 1) 112

(S)-2-(4-(2-ethyl-3-((4- (4-fluorophenyl)thiazol- 2- yl)(methyl)amino)imidazo[1,2-a]pyridin- 6-yl)piperidin-1-yl)-1- (3-hydroxypyrrolidin-1-yl)ethanone F8 (Gen- 10-c) 562 563 (M + 1) 113

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin- 6-yl)piperidin-1-yl)-1- (3-(hydroxymethyl)azetidin-1-yl) ethanone F8 (Gen- 10-c) 562 563 (M + 1) 114

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperidin-1-yl)-N,N- dimethylacetamide F8(Gen- 10-c) 520 521 (M + 1) 115

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperidin-1-yl)-1- (pyrrolidin-1-yl)ethanone F8 (Gen- 10-c) 546 547 (M + 1) 116

(S)-1-(2-(4-(2-ethyl-3- ((4-(4- fluorophenyl)thiazol-2-yl)(methyl)amino) imidazol[1,2-a]pyridin- 6-yl)piperidin-1-yl)acetoyl)pyrrolidine-3- carbonitrile F8 (Gen- 10-c) 571 572 (M + 1)117

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperidin-1-yl)-1-(3- (hydroxymethyl)pyrrolidin-1-yl)ethanone F8 (Gen- 10-c) 576 577 (M + 1) 118

4-((4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin- 6-yl)piperidin-1- yl)methyl)-1,3-dioxolan- 2-oneF8 (Gen- 10-c) 535 535 (M + 1) 119

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperidin-1-yl)-N-(2- hydroxyethyl)-N-methylacetamide F8 (Gen- 10-c) 550 551 (M + 1) 120

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperidin-1-yl)-N- methoxy-N-methylacetamide F8 (Gen- 10-c) 536 537 (M + 1) 121

N-(cyanomethyl)-2-(4- (2-ethyl-3-((4-(4- fluorophenyl)thiazol-2-yl)(methyl)amino) imidazo[1,2-a]pyridin-6- yl)piperidin-1-yl)-N-methylacetamide F8 (Gen- 10-c) 545 546 (M + 1) 122

5-((4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperidin-1- yl)methyl)oxazolidin-2- one F8(Gen- 10-c) 534 536 (M + 1) 123

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperidin-1-yl)-N-(3-hydroxypropyl)acetamide F8 (Gen- 10-c) 550 551 (M + 1) 124

1-(3,3-difluoroazetidin- 1-yl)-2-(4-(2-ethyl-3- ((4-(4-fluorophenyl)thiazol-2- yl)(methyl)amino) imidazo[1,2-a]pyridin-6-yl)piperidin-1- yl)ethanone F8 (Gen- 10-c) 568 569 (M + 1) 125

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperidin-1- yl)acetamide F8 (Gen- 10-c) 492493 (M + 1) 126

1-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a] pyridin-6-yl)piperidin- 1-yl)-2- (pyrrolidin-1-yl)ethanone F9b- F12a (Gen- 10-c) 546 547 (M + 1) 127

1-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperidin-1-yl)-2- (methylamino)ethanoneF9b- F12a (Gen- 10-c) 506 507 (M + 1) 128

1-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperidin-1-yl)-2-(3- hydroxyazetidin-1-yl)ethanone F9b- F12a (Gen- 10c) 548 549 (M + 1) 129

2-(dimethylamino)-1-(4- (2-ethyl-3-((4-(4- fluorophenyl)thiazol-2-yl)(methyl)amino) imidazo[1,2-a]pyridin-6- yl)piperidin-1- yl)ethanoneF9b- F12a (Gen- 10-c) 520 521 (M + 1) 130

3-(dimethylamino)-1-(4- (2-ethyl-3-((4-(4- fluorophenyl)thiazol-2-yl)(methyl)amino) imidazo[1,2-a]pyridin-6- yl)piperidin-1-yl)propan-1-one F9b- F12a (Gen- 10-c) 534 535 (M + 1) 131

2-(3,3-dimethylazetidin- 1-yl)-1-(4-(2-ethyl-3- ((4-(4-fluorophenyl)thiazol-2- yl)(methyl)amino) imidazo[1,2-a]pyridin-6-yl)piperidin-1- yl)ethanone F9b- F12a (Gen- 10-c) 568 569 (M + 1) 132

1-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperidin-1-yl)-3- (methylamino)propan-1-one F9b- F12a (Gen- 10-c) 520 521 (M + 1) 133

1-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperidin-1-yl)-2-(3- fluoroazetidin-1-yl)ethanone F9b- F12a (Gen- 10-c) 550 551 (M + 1) 134

1-(3-(4-(2-ethyl-3-((4- (4-fluorophenyl) thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperidin-1- yl)azetidin-1- yl)ethanone F10-F5b- F9 (Gen- 10-c) 532 533 (M + 1) 135

5-bromo-N-(2-ethyl-6- (1- (methylsulfonyl) piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-4- (4-fluorophenyl)-N- methylthiazol-2-amine F16a(Cpd 80) 592 593 (M + 1) 136

2-((2-ethyl-6-(1- (methylsulfonyl) piperidin-4-yl)imidazo[1,2-a]pyridin-3- yl)(methyl)amino)-4- (4-fluorophenyl)thiazole-5-carbonitrile F17 (Cpd 135) 538 539 (M + 1) 137

2-((2-ethyl-6-(1- (methylsulfonyl) piperidin-4-yl)imidazo[1,2-a]pyridin-3- yl)(methyl)amino)-4-(4- fluorophenyl)thiazole-5-carboxamide see Cpd 137 (Cpd 136) 556 557 (M + 1) 138

2-((2-ethyl-6-(4-(2-(3- hydroxyazetidin-1-yl)- 2-oxoethyl)piperazin-1-yl)imidazo[1,2-a] pyridin-3- yl)(methyl)amino)-4-(4-fluorophenyl)thiazole- 5-carbonitrile F16a- F17 (Cpd 24) 574 575 (M + 1)139

2-((2-ethyl-6-(4-(2-(3- (hydroxymethyl) azetidin-1-yl)-2-oxoethyl)piperazin-1- yl)imidazo[1,2-a] pyridin-3- yl)(methyl)amino)-4-(4-fluorophenyl) thiazole-5- carbonitrile F16a- F17 (Cpd 34) 588 589(M + 1) 140

2-(4-(3-((5-cyano-4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)-2-ethylimidazo[1,2-a] pyridin-6- yl)piperazin-1-yl)-N,N- dimethylacetamideF16a- F17 (Cpd 35) 546 547 (M + 1) 141

2-((2-ethyl-6-(1-(2-(3- hydroxyazetidin-1-yl)-2- oxoethyl)piperidin-4-yl)imidazo[1,2-a] pyridin-3- yl)(methyl)amino)-4-(4-fluorophenyl)thiazole- 5-carbonitrile F16a- F17 (Cpd 110) 573 574(M + 1) 142

(R)-2-((2-ethyl-6-(1-(2- (3-hydroxypyrrolidin-1- yl)-2-oxoethyl)piperidin-4- yl)imidazo[1,2-a] pyridin-3-yl)(methyl)amino)-4-(4- fluorophenyl)thiazole-5- carbonitrile F16a- F17(Cpd 111) 587 588 (M + 1) 143

(S)-2-((2-ethyl-6-(1-(2- (3-hydroxypyrrolidin- 1-yl)-2-oxoethyl)piperidin-4- yl)imidazo[1,2-a] pyridin-3-yl)(methyl)amino)-4-(4- fluorophenyl)thiazole-5- carbonitrile F16a- F17(Cpd 112) 587 588 (M + 1) 144

2-((2-ethyl-6-(1-(2-(3- (hydroxymethyl)azetidin- 1-yl)-2-oxoethyl)piperidin-4- yl)imidazo[1,2-a] pyridin-3-yl)(methyl)amino)-4-(4- fluorophenyl)thiazole-5- carbonitrile F16a- F17(Cpd 113) 587 588 (M + 1) 145

2-(4-(3-((5-cyano-4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)-2-ethylimidazo[1,2-a] pyridin-6-yl)piperidin- 1-yl)-N,N- dimethylacetamideF16a- F17 (Cpd 114) 545 546 (M + 1) 146

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)-5- (hydroxymethyl) thiazol-2-yl)(methyl)amino) imidazo[1,2-a]pyridin-6- yl)piperazin-1-yl)-1-(3-(hydroxymethyl)azetidin- 1-yl)ethanone F14 (Cpd 34) 593 594 (M + 1) 147

(2-((2-ethyl-6-(1- (methylsulfonyl) piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl) (methyl)amino)-4-(4- fluorophenyl)thiazol-5-yl)methanol F14 (Cpd 80) 543 544 (M + 1) 148

(2-((2-ethyl-6-(1- (methylsulfonyl) piperidin-4-yl)imidazo[1,2-a]pyridin-3- yl)(methyl)amino)-4-(4- (trifluoromethoxy)phenyl)thiazol-5-yl) methanol F14 (Cpd 85) 609 610 (M + 1) 149

(2-((6-(1-(3- (dimethylamino)propyl- sulfonyl)piperidin-4-yl)-2-ethylimidazo[1,2-a] pyridin-3-yl)(methyl) amino)-4-(4-fluorophenyl)thiazol-5- yl) F14 (Cpd 87) 614 615 (M + 1) 150

(2-((2-ethyl-6-(1- (methylsulfonyl) piperidin-4-yl)imidazo[1,2-a]pyridin-3- yl)(methyl)amino)-4-(4- (trifluoromethyl)phenyl)thiazol-5-yl) methanol F14 (Cpd 84) 593 594 (M + 1) 151

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)-5- (hydroxymethyl) thiazol-2-yl)(methyl)amino) imidazo[1,2-a]pyridin- 6-yl)piperidin-1-yl)-1-(pyrrolidin-1- yl)ethanone F14 (Cpd 115) 576 577 (M + 1) 152

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)-5- (hydroxymethyl)thiazol- 2-yl)methyl)amino) imidazo[1,2-a]pyridin-6- yl)piperidin-1-yl)-1-(3-(hydroxymethyl) azetidin-1-yl)ethanone F14 (Cpd 113) 592 593 (M + 1) 153

2-(dimethylamino)-1-(4- (2-ethyl-3-((4-(4- fluorophenyl)-5-(hydroxymethyl) thiazol-2- yl)(methyl)amino) imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl) ethanone F14 (Cpd 129) 550 551 (M + 1) 154

1-(4-(2-ethyl-3-((4-(4- fluorophenyl)-5- (hydroxymethyl)thiazol- 2-yl)(methyl)amino) imidazo[1,2-a]pyridin-6- yl)piperidin-1-yl)propan-1-one F9b- F14 (Gen- 10-c) 521 522 (M + 1) 155

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)-5- (hydroxymethyl) thiazol-2-yl)(methyl)amino) imidazo[1,2-a]pyridin-6- yl)piperazin-1-yl)-N,N-dimethylacetamide B1- C1- F1b- D1- F7- E1- F18- F5b- F8 (Gen- 10-ag) 551552 (M + 1) 156

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)-5- (hydroxymethyl)thiazol- 2-yl)(methyl)amino) imidazo[1,2-a]pyridin-6- yl)piperidin-1-yl)-1-(3-hydroxyazetidin-1- yl)ethanone F18- F5b- F8 (Gen- 10-ar) 578 579 (M + 1)157

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)-5- (hydroxymethyl)thiazol- 2-yl)(methyl)amino) imidazo[1,2-a]pyridin- 6-yl)piperidin-1-yl)-N,N-dimethylacetamide F18- F5b- F8 (Gen- 10-ar) 550 N.M 158

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)-5-(2,2,2-trifluoroacetoyl)thiazol- 2- yl)(methyl)amino) imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-N,N- dimethylacetamide F15 (Cpd 35) 617 618 (M + 1)159

1-(2-((2-ethyl-6-(1-(2- (3-hydroxyazetidin-1- yl)-2-oxoethyl)piperidin-4- yl)imidazo[1,2-a] pyridin-3-yl)(methyl)amino)-4-(4- fluorophenyl)thiazol-5- yl)-2,2,2-trifluoroethanone F15 (Cpd 110) 644 645 (M + 1) 160

1-(2-((2-ethyl-6-(1- (methylsulfonyl) piperidin-4-yl)imidazo[1,2-a]pyridin-3- yl)(methyl)amino)-4-(4- fluorophenyl)thiazol-5-yl)-2,2,2- trifluoroethanone F15 (Cpd 80) 609 610 (M + 1) 161

2-(2-((2-ethyl-6- (piperazin-1- yl)imidazo[1,2-a] pyridin-3-yl)(methyl)amino)-5- methylthiazol-4-yl)-5- fluorobenzonitrile F1a (Gen-5-m) 475 476 (M + 1) 162

2-(2-((2-ethyl-6-(4-(2- (3-hydroxyazetidin-1- yl)-2-oxoethyl)piperazin-1- yl)imidazo[1,2-a] pyridin-3- yl)(methyl)amino)-5-methylthiazol-4-yl)-5- fluorobenzonitrile F8 (Cpd 161) 588 589 (M + 1)163

2-(4-(3-((4-(2-cyano-4- fluorophenyl)-5- methylthiazol-2-yl)(methyl)amino)-2- ethylimidazo[1,2-a] pyridin-6-yl)piperazin-1-yl)-N- methylacetamide F8 (Cpd 161) 546 547 (M + 1) 164

2-(2-((2-ethyl-6-(4-(2- (3-fluoroazetidin-1-yl)- 2-oxoethyl)piperazin-1-yl)imidazo[1,2-a] pyridin-3- yl)(methyl)amino) thiazol-4-yl)-5-fluorobenzonitrile F8 (Gen- 10-i) 576 577 (M + 1) 165

2-(2-((6-(4-(2-(3,3- difluoroazetidin-1-yl)-2- oxoethyl)piperazin-1-yl)-2-ethylimidazo[1,2- a]pyridin-3- yl)(methyl)amino) thiazol-4-yl)-5-fluorobenzonitrile F8 (Gen- 10-i) 594 595 (M + 1) 166

2-(2-((2-ethyl-6-(4-(2- (3-hydroxyazetidin-1- yl)-2-oxoethyl)piperazin-1- yl)imidazo[1,2-a] pyridin-3- yl)(methyl)amino)thiazol-4-yl)-5- fluorobenzonitrile F8 (Gen- 10-i) 574 575 (M + 1) 167

2-(2-((6-(4-(2-(azetidin- 1-yl)-2- oxoethyl)piperazin-1-yl)-2-ethylimidazo[1,2- a]pyridin-3- yl)(methyl)amino) thiazol-4-yl)-5-fluorobenzonitrile F8 (Gen- 10-i) 558 559 (M + 1) 168

2-(4-(3-((4-(2-cyano-4- fluorophenyl)thiazol-2- yl)(methyl)amino)-2-ethylimidazo[1,2-a] pyridin-6- yl)piperazin-1-yl)-N,N- dimethylacetamideF8 (Gen- 10-i) 546 547 (M + 1) 169

2-(4-(3-((4-(2-cyano-4- fluorophenyl)thiazol-2- yl)(methyl)amino)-2-ethylimidazo[1,2-a] pyridin-6- yl)piperazin-1-yl)-N- methylacetamide F8(Gen- 10-i) 532 533 (M + 1) 170

2-(2-((2-ethyl-6-(1-(2- (3-hydroxyazetidin-1- yl)-2-oxoethyl)piperidin-4- yl)imidazo[1,2-a] pyridin-3- yl)(methyl)amino)thiazol-4-yl)-5- fluorobenzonitrile F8 (Gen- 10-h) 573 575 (M + 1) 171

2-(4-(3-((4-(2-cyano-4- fluorophenyl)thiazol-2- yl)(methyl)amino)-2-ethylimidazo[1,2-a] pyridin-6-yl)piperidin- 1-yl)-N,N- dimethylacetamideF8 (Gen- 10-h) 545 546 (M + 1) 172

2-(2-((2-ethyl-6-(1-(2- (3-hydroxyazetidin-1- yl)-2-oxoethyl)piperidin-4- yl)imidazo[1,2-a] pyridin-3- yl)(methyl)amino)-5-methylthiazol-4-yl)-5- fluorobenzonitrile F8 (Gen- 10-f) 587 588 (M + 1)173

2-(5-((2-ethyl-6-(1-(2- (3-hydroxyazetidin-1- yl)-2-oxoethyl)piperidin-4- yl)imidazo[1,2-a] pyridin-3- yl)(methyl)amino)-1,2,4-thiadiazol-3-yl)-5- fluorobenzonitrile F8 (Gen- 10-t) 574 575(M + 1) 174

2-(4-(2-(2-cyanoethyl)- 3-((4-(4- fluorophenyl)thiazol-2-yl)(methyl)amino) imidazo[1,2-a]pyridin-6- yl)piperidin-1-yl)-N,N-dimethylacetamide see Cpd 174- F8 (Gen- 10-aa) 545 546 (M + 1) 175

3-(3-((4-(4- fluorophenyl)-5- (hydroxymethyl)thiazol-2-yl)(methyl)amino)-6- (1- (methylsulfonyl) piperidin-4-yl)imidazo[1,2-a]pyridin-2- yl)propanenitrile F11- F14 (Gen- 10-aa) 568 569(M + 1) 176

3-(6-(1-(2- (dimethylamino)-2- oxoethyl)piperidin-4- yl)-3-((4-(4-fluorophenyl)thiazol-2- yl)(methyl)amino) imidazo[1,2-a]pyridin-2-yl)propanamide see Cpd 175- F5b- F8 (Gen- 10-am) 563 564 (M + 1) 177

N-(6-(3-aminoazetidin- 1-yl)-2- ethylimidazo[1,2-a] pyridin-3-yl)-4-(4-fluorophenyl)-N- methylthiazol-2-amine F1b- F5a (Gen- 5-b) 422 423(M + 1) 178

2-(1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)azetidin-3-ylamino)- 1-(3-hydroxyazetidin-1-yl)ethanone F8 (Cpd 177) 535 536 (M + 1) 179

N-(1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)azetidin-3-yl)-2-(3- hydroxyazetidin-1-yl)acetamide F9b- F8 (Cpd 177) 535 536 (M + 1) 180

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperazin-1- yl)ethanol F1b (Gen- 5b) 480 481(M + 1) 181

N-(2-ethyl-6- morpholinoimidazo[1,2- a]pyridin-3-yl)-4-(4-fluorophenyl)-N- methylthiazol-2-amine F1b (Gen- 5-b) 437 438 (M + 1)182

4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)-thiomorpholine 1,1- dioxide F1b (Gen- 5-c)485 486 (M + 1) 183 (or Gen- 10-a)

1-(3-((4-(4- chlorophenyl)thiazol-2- yl)(methyl)amino)-2-ethylimidazo[1,2- a]pyridin-6- yl)imidazolidin-2-one F4 (Gen- 5-i) 452(³⁵Cl), 454 (³⁷Cl) 453 (³⁵Cl M + 1) 455 (³⁷Cl M + 1) 184

ethyl 2-(3-(3-((4-(4- chlorophenyl)thiazol-2- yl)(methyl)amino)-2-ethylimidazo[1,2-a] pyridin-6-yl)-2- oxoimidazolidin-1- yl)acetate seeCpd 184- F8 (Cpd 183) 538 (³⁵Cl), 540 (³⁷Cl) 539 (³⁵Cl M + 1) 541 (³⁷ClM + 1) 185

4-(4-chlorophenyl)-N- methyl-N-(6-(1- (methylsulfonyl)- 1,2,3,6-tetrahydropyridin-4-yl)- 2-(2,2,2- tetrahydropyridin-4-yl)- 2-(2,2,2-trifluoroethyl)imidazo [1,2-a]pyridin-3-yl) thiazol-2-amine F11 (Gen-10- ad) 581 (³⁵Cl), 583 (³⁷Cl) NA 186

2-(2-((2-ethyl-6-(1- (methylsulfonyl) piperidin-4-yl)imidazo[1,2-a]pyridin-3- yl)(methyl)amino)-4-(4- fluorophenyl)thiazol-5-yl)acetonitrile see cpd 186 (Cpd 147) 552 553 (M + 1) 187

2-ethyl-N-(4-(4- fluorophenyl)pyrimidin- 2-yl)-N-methyl-6-(1-(methylsulfonyl)- 1,2,3,6- tetrahydropyridin-4- yl)imidazo[1,2-a]pyridin-3-amine See Cpd 187 (Gen- 9-a) 506 507 (M + 1) 188

3-(4-chlorophenyl)-N- (2-ethyl-6-(4- (methylsulfonyl) piperazin-1-yl)imidazo[1,2-a] pyridin-3-yl)-N- methyl-1,2,4-thiadiazol- 5-amine F11(Gen- 10-u) 531 (³⁵Cl), 533 (³⁷Cl) 532 (³⁵Cl M + 1) 534 (³⁷Cl M + 1) 189

N-(2-ethyl-6-(1- (methylsulfonyl)- 1,2,3,6- tetrahydropyridin-4-yl)imidazo[1,2-a] pyridin-3-yl)-3-(4- fluorophenyl)-N-methyl-1,2,4-oxadiazol- 5-amine F2 (Gen- 5-ae) 496 497 (M + 1) 190

2-(4-(2-ethyl-3-((3-(4- fluorophenyl)-1,2,4- thiadiazol-5-yl)(methyl)amino) imidazo[1,2-a]pyridin- 6-yl)-5,6-dihydropyridin-1(2H)-yl)-N,N- dimethylacetamide F8 (Gen- 10-v) 519 520 (M + 1) 191

2-(4-(2-ethyl-3-((3-(4- fluorophenyl)-1,2,4- thiadiazol-5-yl)(methyl)amino) imidazo[1,2-a]pyridin-6- yl)piperidin-1-yl)-N,N-dimethylacetamide F8 (gen- 10-w) 521 522 (M + 1) 192

N-(6-(4-((1H-imidazol- 5-yl)methyl)piperazin-1- yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4- fluorophenyl)-N- methylthiazol-2-amine F10- (Gen-10-e) 516 517 (M + 1) 193

N-(2-ethyl-6-(1- (methylsulfonyl)- 1,2,3,6- tetrahydropyridin-4-yl)imidazo[1,2-a] pyridin-3-yl)-N- methyl-4-(4- (trifluoromethyl)phenyl)thiazol-2-amine F11 (Gen- 10-ai) 561 562 (M + 1) 194

N-cyclopropyl-2-(4-(2- ethyl-3-((4-(4- fluorophenyl)thiazol-2-yl)(methyl)amino) imidazo[1,2-a]pyridin-6- yl)piperidin-1- yl)acetamideF8 (Gen- 10-c) 532 533 (M + 1) 195

5-((4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin- 6-yl)piperidin-1- yl)methyl)-3-methyloxazolidin-2-one F8 (Gen- 10-c) 548 549 (M + 1) 196

(R)-5-((4-(2-ethyl-3-((4- (4-fluorophenyl)thiazol- 2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperidin-1- yl)methyl)oxazolidin-2- one F8(Gen- 10-c) 534 535 (M + 1) 197

(S)-5-((4-(2-ethyl-3-((4- (4-fluorophenyl)thiazol- 2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperidin-1- yl)methyl)oxazolidin-2- one F8(Gen- 10-c) 534 535 (M + 1) 198

4-((4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperidin-1- yl)methyl)oxazolidin-2- one F8(Gen- 10-c) 534 535 (M + 1) 199

N-(2-ethyl-6-(1- (methylsulfonyl)- 1,2,3,6- tetrahydropyridin-4-yl)imidazo[1,2-a] pyridin-3-yl)-3-(4- fluorophenyl)-N-methyl-1,2,4-thiadiazol- 5-amine F11 (Gen- 10-v) 512 513 (M + 1) 200

1-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperazin-1- yl)propane-1,2-dione F9a (Gen-10-e) 506 507 (M + 1) 201

5-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperazine-1- carbonyl)pyrrolidin-2- one F9a(Gen- 10-e) 547 548 (M + 1) 202

(1-aminocyclopropyl)(4- (2-ethyl-3-((4-(4- fluorophenyl)thiazol-2-yl)(methyl)amino) imidazo[1,2-a]pyridin-6- yl)piperazin-1- yl)methanonesee Cpd 202 (Gen- 10-e) 519 520 (M + 1) 203

(S)-1-(4-(2-ethyl-3-((4- (4-fluorophenyl)thiazol- 2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperazin-1-yl)-2- hydroxypropan-1-one F9a(Gen- 10-e) 508 509 (M + 1) 204

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperazin-1-yl)-2- oxoacetamide see Cpd 204(Gen- 10-an) 507 508 (M + 1) 205

1-benzyl-4-(4-(2-ethyl- 3-((4-(4- fluorophenyl)thiazol-2-yl)(methyl)amino) imidazo[1,2-a]pyridin-6- yl)piperazine-1-carbonyl)pyrrolidin-2- one F9a (Gen- 10-e) 637 638 (M + 1) 206

3-(3-((4-(4- chlorophenyl)thiazol-2- yl)(methyl)amino)-2-ethylimidazo[1,2-a] pyridin-6- yl)oxazolidin-2-one F4 (Gen- 5-i) 453(³⁵Cl), 455 (³⁷Cl) 454 (³⁵Cl M + 1) 456 (³⁷Cl M + 1) 207

2-(2-ethyl-4-((4-(4- chlorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin- 6-yl)-1- [1,2]thiazinane-1,1- dioxide F4 (Gen-5-i) 501 (³⁵Cl), 503 (³⁷Cl) 502 (³⁵Cl M + 1) 504 (³⁷Cl M + 1) 208

4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)-N-(thiophen-2-yl)- 5,6-dihydropyridine-1(2H)-carboxamide F2 (Gen- 5-b) 558 559 (M + 1) 209

4-(4-chlorophenyl)-N- (2-ethyl-6-(1- (methylsulfonyl)- 1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a] pyridin-3-yl)-N-methylthiazol-2-amine F11 (Gen- 10-ak) 527 (³⁵Cl), 529 (³⁷Cl) 528 (³⁵ClM + 1), 530 (³⁷Cl M + 1) 210

4-(4-chlorophenyl)-N- (2-ethyl-6-(1- (trifluoromethylsulfonyl)- 1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2- a]pyridin-3-yl)-N-methylthiazol-2-amine F11 (Gen- 10-ak) 581 (³⁵Cl), 583 (³⁷Cl) 582 (³⁵ClM + 1), 584 (³⁷Cl M + 1) 211

1-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperidin-4-ol see Cpd 211 (Gen- 10-aq) 451452 (M + 1) 212

2-(4-(3-((4-(4- chlorophenyl)thiazol-2- yl)(methyl)amino)-2-ethylimidazo[1,2- a]pyridin-6- yl)piperazin-1- yl)ethanol F1b (Gen- 5-y)496 497 (M + 1) 213

4-(2-ethyl-3-((4-(4- chlorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin- 6-yl)-thiomorpholin- 1,1-dioxide F1b (Gen- 5-y)501 502 (M + 1) 214

tert-butyl 4-(2-ethyl-3- ((4-(4- fluorophenyl)thiazol-2-yl)(methyl)amino) imidazo[1,2-a] pyridin-6-yl)- 5,6-dihydropyridine-1(2H)-carboxylate F2 (Gen- 5-b) 533 534 (M + 1) 215

1-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperidin-1- yl)propan-1-one F9b- F6 (Gen-10-b) 491 492 (M + 1) 216 (Gen- 10-c)

N-(2-ethyl-6-(piperidin- 4-yl)imidazo[1,2- a]pyridin-3-yl)-4-(4-fluorophenyl)-N- methylthiazol-2-amine E1- F6- F5a (Gen- 9-c) 435 436(M + 1) 217

N-(6-(1- benzylpiperidin-4-yl)-2- ethylimidazo[1,2-a]pyridin-3-yl)-4-(4- fluorophenyl)-N- methylthiazol-2-amine F10 (Gen-10-c) 525 526 (M + 1) 218

N-(2-ethyl-6-(1- isopropylpiperidin-4- yl)imidazo[1,2-a]pyridin-3-yl)-4-(4- fluorophenyl)-N- methylthiazol-2-amine F10 (Gen-10-c) 477 478 (M + 1) 219

tert-butyl 4-(2-ethyl-3- ((4-(4- fluorophenyl)thiazol-2-yl)(methyl)amino) imidazo[1,2-a]pyridin-6- yl)piperidine-1- carboxylateF2-F6 (Gen- 5-c) 535 536 (M + 1) 220

N-(6-(3,6-dihydro-2H- pyran-4-yl)-2- ethylimidazo[1,2-a]pyridin-3-yl)-4-(4- fluorophenyl)-N- methylthiazol-2-amine F2 (Gen-5-b) 434 435 (M + 1) 221

4-(4-chlorophenyl)-N- (6-(3,6-dihydro-2H- pyran-4-yl)-2-ethylimidazo[1,2-a] pyridin-3-yl)-N- methylthiazol-2-amine F2 (Gen- 5-i)450 (³⁵Cl), 452 (³⁷Cl) 451 (³⁵Cl M + 1) 453 (³⁷Cl M + 1) 222

(2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperidin-1-yl)-4,5- dihydrooxazol-5-yl)methanol see Cpd 222 (Gen- 10-c) 534 535 (M + 1) 223

2-(4-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin-6- yl)piperidin-1-yl)-1-(3- hydroxypyrrolidin-1-yl)ethanone F8 (Gen- 10-c) 562 563 (M + 1) 224

2-(2-((2-ethyl-6-(1- (methylsulfonyl) piperidin-4-yl)imidazo[1,2-a]pyridin-3- yl)(methyl)amino) thiazol-4-yl)-5- fluorophenol E1(Gen- 9-b) 529 530 (M + 1) 225

tert-butyl 4-(3-((3-(4- chlorophenyl)-1,2,4- thiadiazol-5-yl)(methyl)amino)-2- ethylimidazo[1,2-a] pyridin-6-yl) piperazine-1-carboxylate F1b (Gen- 5-w) 553 (³⁵Cl), 555 (³⁷Cl) 554 (³⁵Cl M + 1), 556(³⁷Cl M + 1) 226

N-(6-(4-((1H-imidazol- 2-yl)methyl)piperazin-1- yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4- fluorophenyl)-N- methylthiazol-2-amine F10 (Gen-10-e) 516 517 (M + 1) 227

cyclopropyl(4-(2-ethyl- 3-((4-(4- fluorophenyl)thiazol-2-yl)(methyl)amino) imidazo[1,2-a]pyridin- 6-yl)piperazin-1-yl) methanonesee Cpd 227 (Gen- 10-e) 504 505 (M + 1) 228

ethyl 2-(4-(2-ethyl-3- ((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin- 6-yl)piperazin-1-yl)-2- oxoacetate F9b (Gen-10-e) 536 537 (M + 1) 229

[6-(1,1-Dioxo- isothiazolidin-2-yl)-2- ethyl-imidazo[1,2-a]pyridin-3-yl]-[4-(4- fluoro-phenyl)-thiazol- 2-yl]-methyl-amine see Cpd229 (Gen- 10-ao) 471 472 (M + 1) 230

tert-butyl 4-(3-((4-(4- chlorophenyl)thiazol-2- yl)(methyl)amino)-2-ethylimidazo[1,2-a] pyridin-6-yl)-5,6- dihydropyridine-1(2H)-carboxylate F2 (Gen- 5-i) 549 (³⁵Cl), 551 (³⁷Cl) 550 (³⁵Cl M + 1), 552(³⁷Cl M + 1) 231 (Gen- 10- g)

4-(4-chlorophenyl)-N- (6-(3,6-dihydro-2H- thiopyran-4-yl)-2-ethylimidazo[1,2-a] pyridin-3-yl)-N- methylthiazol-2-amine F2 (Gen- 5-i)466 (³⁵Cl), 468 (³⁷Cl) N.M. 232

N-(6-(4,4- difluoropiperidin-1-yl)- 2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4- fluorophenyl)-N- methylthiazol-2-amine F1b (Gen-5-c) 471 472 233

N-(6-(1-(3- chloropropylsulfonyl)- 1,2,3,6- tetrahydropyridin-4-yl)-2-ethylimidazo[1,2-a] pyridin-3-yl)-4-(4- fluorophenyl)-N-methylthiazol-2-amine F11 (Gen- 10-b) 573 (³⁵Cl), 575 (³⁷Cl) 574 (³⁵ClM + 1), 576 (³⁷Cl M + 1) 234

tert-butyl 4-(3-((4-(4- chlorophenyl)thiazol-2- yl)(methyl)amino)-2-ethylimidazo[1,2-a] pyridin-6- yl)piperazine-1- carboxylate F1b (Gen-5-y) 552 (³⁵Cl), 554 (³⁷Cl) 553 (³⁵Cl M + 1), 555 (³⁷Cl M + 1) 235

N-(6-(1- (cyclohexylmethyl) piperidin-4-yl)-2- ethylimidazo[1,2-a]pyridin-3-yl)-4-(4- fluorophenyl)-N- methylthiazol-2-amine F10 (Gen-10-c) 531 532 (M + 1) 236

N-(2-ethyl-6-(5-methyl- 4,5-dihydrooxazol-2- yl)imidazo[1,2-a]pyridin-3-yl)-4-(4- fluorophenyl)-N- methylthiazol-2-amine F13- F9a-F19 (Gen- 5-aa) 435 436 (M + 1) 237

N-(2-ethyl-6-(4-methyl- 4,5-dihydrooxazol-2- yl)imidazo[1,2-a]pyridin-3-yl)-4-(4- fluorophenyl)-N- methylthiazol-2-amine F13- F9a-F19 (Gen- 5-aa) 435 436 (M + 1) 238

2-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin- 6-yl)-4,5-dihydro- oxazole-4- carboxylic acidF13- F9a- F19 (Gen- 5-aa) 465 466 (M + 1) 239

(2-(2-ethyl-3-((4-(4- fluorophenyl)thiazol-2- yl)(methyl)amino)imidazo[1,2-a]pyridin- 6-yl)-4,5-dihydro- oxazol-4- yl)methanol F13-F9a- F19 (Gen- 5-aa) 451 452 (M + 1) 240

4-(4-chlorophenyl)-N- (6-(4,5-dihydrooxazol- 2-yl)-2- ethylimidazo[1,2-a]pyridin-3-yl)-N- methylthiazol-2-amine F13- F9a- F19 (Gen- 5-ag) 437(³⁵Cl), 439 (³⁷Cl) 438 (³⁵Cl M + 1), 440 (³⁷Cl M + 1)

TABLE IV NMR data of the compounds of the invention. Cpd NMR data (δ) 1¹H NMR (400 MHz, CDCl₃) δ ppm 8.23-8.13 (2 H, m), 7.24-7.14 (2 H, m),7.00 (2 H, d), 3.62 (3 H, s), 3.09 (8 H, bs), 2.77 (2 H, q), 2.62 (3 H,s), 1.35 (3 H, t) 2 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.20-8.12 (2 H, m),7.22-7.13 (2 H, m), 6.99 (2 H, s), 4.68 (1 H, m), 4.43 (1 H, dd), 4.26(1 H, dd), 4.14-4.05 (1 H, m), 3.88 (1 H, dd), 3.61 (3 H, s), 3.58-3.52(1 H, m), 3.14-3.02 (6 H, m), 2.74 (2 H, q), 2.70-2.62 (4 H, m), 2.59 (3H, s), 1.33 (3 H, t) 3 ¹H NMR (300 MHz, CDCl₃) δ ppm 8.22-8.08 (2 H, m),7.17 (2 H, t), 6.99 (2 H, s), 4.24-4.03 (2 H, m), 3.94 (2 H, s), 3.61 (3H, s), 3.09 (6 H, bs.), 2.82-2.64 (6 H, m), 2.60 (3 H, s), 1.53 (3 H,s), 1.33 (3 H, t) 4 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.21-8.12 (2 H, m),7.17 (2 H, t), 6.99 (2 H, s), 4.58-4.45 (1 H, m), 3.71-3.48 (7 H, m),3.23-3.15 (2 H, m), 3.09 (4 H, bs), 2.78-2.69 (6 H, m), 2.60 (3 H, s),2.07-2.00 (1 H, m), 2.00-1.90 (1 H, m), 1.33 (3 H, t) 5 ¹H NMR (400 MHz,CDCl₃) δ ppm 8.21-8.12 (2 H, m), 7.24-7.12 (2 H, m), 6.99 (2 H, s),4.57-4.46 (1 H, m), 3.70-3.53 (7 H, m), 3.28-3.04 (6 H, m), 2.83-2.67 (6H, m), 2.62 (3 H, s), 2.10-2.00 (1 H, m), 1.99-1.89 (1 H, m), 1.34 (3 H,t) 6 ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.25-7.99 (2 H, m), 7.33-7.06 (4 H,m), 4.62-4.49 (2 H, m), 4.19 (1 H, dd), 4.15-4.08 (1 H, m), 3.75 (1 H,dd), 3.64 (3 H, s), 3.21-3.02 (4 H, m), 2.88 (2 H, s), 2.79-2.66 (4 H,m), 2.55 (3 H, s), 1.32 (3 H, t), 1.14 (6 H, s) 7 ¹H NMR (300 MHz,MeOD-d₄) δ ppm 7.95-7.84 (2 H, m), 7.22-7.16 (2 H, m), 7.11 (2 H, t),6.94 (1 H, s), 4.61-4.51 (1 H, m), 4.50-4.41 (1 H, m), 4.20 (1 H, dd),4.04 (1 H, dd), 3.75 (1 H, dd), 3.60 (3 H, s), 3.17-3.01 (6 H, m), 2.72(2 H, q), 2.65 (4 H, bt), 2.55 (3 H, s), 1.31 (3 H, t) 8 ¹H NMR (400MHz, MeOD-d₄) δ ppm 7.89 (2 H, dd), 7.19 (2 H, d), 7.11 (2 H, t), 6.93(1 H, s), 4.46-4.35 (1 H, m), 3.69-3.43 (7 H, m), 3.27-3.18 (2 H, m),3.17-3.03 (4 H, m), 2.76-2.65 (6 H, m), 2.55 (3 H, s), 2.10-1.83 (2 H,m), 1.31 (3 H, t) 9 ¹H NMR (300 MHz, MeOD-d₄) δ ppm 7.97-7.89 (2 H, m),7.20 (2 H, bs), 7.13 (2 H, t), 6.95 (1 H, s), 4.48-4.39 (1 H, m),3.71-3.42 (7 H, m), 3.25 (2 H, d), 3.17-3.04 (4 H, m), 2.76-2.65 (6 H,m), 2.56 (3 H, s), 2.11-1.88 (2 H, m), 1.31 (3 H, t) 10 ¹H NMR (400 MHz,MeOD-d₄) δ ppm 8.27-8.04 (2 H, m), 7.78 (1 H, s), 7.33-7.16 (3 H, m),4.61-4.54 (1 H, m), 4.50 (1 H, dd), 4.25-4.18 (1 H, m), 4.06 (1 H, dd),3.77 (1 H, dd), 3.67 (3 H, s), 3.08 (2 H, d), 3.05-2.96 (2 H, m), 2.76(2 H, qd), 2.59 (4 H, bs), 2.27-2.16 (2 H, m), 1.88-1.78 (4 H, m), 1.34(3 H, t) 11 ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.21-8.18 (2 H, m), 7.96 (1H, s), 7.52 (1 H, s), 7.30 (2 H, t), 6.31 (1 H, bs), 4.37-4.28 (1 H, m),4.14-4.05 (1 H, m), 4.01-3.99 (2 H, m), 3.57-3.50 (2 H, m), 2.94 (3 H,s), 2.86-2.76 (2 H, m), 2.68 (5 H, bs), 1.43 (3 H, t), 1.38 (3 H, t) 12¹H NMR (400 MHz, CDCl₃) δ ppm 8.21-8.13 (2 H, m), 7.22-7.15 (2 H, m),6.97-6.89 (2 H, m), 4.74-4.65 (1 H, m), 4.48-4.40 (1 H, m), 4.33-4.24 (1H, m), 4.14-4.07 (1 H, m), 3.90 (1 H, dd), 3.63 (3 H, bs), 3.17-3.05 (6H, m), 2.79-2.66 (6 H, m), 1.36 (3 H, t) 13 ¹H NMR (300 MHz, CDCl₃) δppm 8.22-8.11 (2 H, m), 7.25-7.13 (2 H, m), 7.02-6.86 (2 H, m), 3.63 (3H, s), 3.13 (6 H, bs), 2.85 (3 H, d), 2.81-2.68 (6 H, m), 1.36 (3 H, t)14 ¹H NMR (400 MHz, CDCl₃) δ ppm) 7.89-7.83 (2 H, m), 7.09 (2 H, t),7.00 (1 H, s), 6.86 (1 H, dd), 6.69 (1 H, s), 4.68 (1 H, bs), 4.47-4.40(1 H, m), 4.57-4.25 (1 H, m), 4.08 (1 H, dd), 3.89 (1 H, dd), 3.60 (3 H,s), 3.11-3.02 (6 H, m), 2.74 (2 H, q), 2.68-2.62 (4 H, m), 1.33 (3 H, t)15 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.89-7.83 (2 H, m), 7.09 (2 H, t), 7.00(1 H, s), 6.87 (1 H, d), 6.69 (1 H, s), 4.58-4.48 (1 H, m), 3.71-3.51 (7H, m), 3.23-3.14 (2 H, m), 3.00-3.12 (4 H, m), 2.78-2.64 (6 H, m),2.12-1.89 (2 H, m), 1.33 (3 H, t) 16 ¹H NMR (300 MHz, MeOD-d₄) δ ppm7.97-7.82 (2 H, m), 7.28-7.17 (2 H, m), 7.11 (2 H, t), 6.98 (1 H, s),4.47-4.33 (1 H, m), 3.73-3.40 (7 H, m), 3.24 (2 H, d), 3.18-3.02 (4 H,m), 2.77-2.61 (6 H, m), 2.14-1.84 (2 H, m), 1.31 (3 H, t) 17 ¹H NMR (300MHz, CDCl₃) δ ppm 7.84-7.79 (2 H, m), 7.52 (1 H, s), 7.34 (1 H, s), 7.04(2 H, t), 6.62 (1 H, s), 4.65-4.58 (1 H, m), 4.41-4.36 (1 H, m),4.24-4.18 (1 H, m), 4.05-4.01 (1 H, m), 3.86-3.81 (1 H, m), 3.55 (3 H,s), 3.01-2.93 (4 H, m), 2.71-2.54 (3 H, m), 2.36 (3 H, s), 2.25-2.13 (2H, m), 2.04-1.57 (4 H, m), 1.28 (3 H, t) 18 ¹H NMR (400 MHz, CDCl₃) δppm 8.18-8.14 (2 H, m), 7.26-7.16 (4 H, m), 4.70-4.68 (1 H, m),4.47-4.43 (1 H, m), 4.30-4.26 (1 H, m), 4.12-4.08 (1 H, m), 3.91-3.87 (1H, m), 3.62 (3 H, s), 3.14-3.06 (6 H, m), 2.73-2.68 (6 H, m), 1.34 (3 H,t) 19 ¹H NMR (400 MHz, DMSO) δ ppm 8.02-7.95 (2 H, m), 7.68 (1 H, d),7.49 (1 H, d), 7.32-7.23 (3 H, m), 4.50-4.32 (2 H, m), 4.09-4.01 (1 H,m), 3.98-3.90 (1 H, m), 3.67-3.52 (4 H, m), 3.10-2.90 (6 H, m),2.68-2.42 (6 H, m), 1.23 (3 H, t) 20 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.17(1 H, s), 7.87-7.83 (2 H, m), 7.37 (1 H, d), 7.10 (2 H, t), 6.69 (1 H,s), 4.55-4.50 (1 H, m), 3.69-3.51 (7 H, m), 3.47-3.12 (2 H, m), 3.06 (4H, bs), 2.80-2.68 (6 H, m), 1.99-2.07 (2 H, m), 1.31 (3 H, t) 21 ¹H NMR(400 MHz, CDCl₃) δ ppm 7.87-7.84 (2 H, m), 7.36-7.23 (2 H, m), 7.10 (2H, t), 6.89 (1 H, s), 4.55-4.50 (1 H, m), 3.69-3.52 (7 H, m), 3.22-3.18(2 H, m), 3.05 (4 H, bs), 2.75-2.67 (6 H, m), 2.10-1.96 (2 H, m), 1.31(3 H, t) 22 ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.19-8.11 (2 H, m),7.51-7.36 (3 H, m), 7.24 (2 H, t), 3.65 (3 H, s), 3.20-3.14 (4 H, m),3.05 (2 H, s), 2.75 (3 H, s), 2.74-2.64 (6 H, m), 1.32 (3 H, t) 23 ¹HNMR (400 MHz, MeOD-d₄) δ ppm 7.92-7.88 (2 H, m), 7.48-7.45 (1 H, m),7.40-7.37 (2 H, m), 7.14-7.09 (2 H, m), 6.95 (1 H, s), 3.61 (3 H, s),3.55 (4 H, t), 3.09-2.96 (4 H, m), 2.69 (2 H, q), 1.45 (9 H, s), 1.31(3H, t) 24 ¹H NMR (400 MHz, MeOD-d₄) δ ppm 7.94-7.84 (2 H, m), 7.44 (1H, d), 7.40-7.29 (2 H, m), 7.11 (2 H, m), 6.94 (1 H, s), 4.58-4.51 (1 H,m), 4.50-4.42 (1 H, m), 4.23-4.16 (1 H, m), 4.04 (1 H, dd), 3.75 (1 H,dd), 3.60 (3 H, s), 3.19-3.00 (6 H, m), 2.73-2.61 (6 H, m), 1.30 (3 H,t) 25 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.94-7.82 (2 H, m), 7.59-7.53 (1 H,m), 7.24-7.04 (4 H, m), 6.70 (1 H, s), 4.60-4.50 (1 H, m), 3.74-3.56 (7H, m), 3.23 (2 H, d), 3.12 (4 H, bs), 2.76 (6 H, m), 2.11-1.92 (2 H, m),1.37 (3 H, t) 26 ¹H NMR (300 MHz, CDCl₃) δ ppm 7.96-7.77 (2 H, m), 7.52(1 H, d), 7.19-7.04 (4 H, m), 6.67 (1 H, s), 4.57-4.45 (1 H, m),3.78-3.52 (7 H, m), 3.19 (2 H, d), 3.14-3.00 (4 H, m), 2.79-2.63 (6 H,m), 2.07-1.98 (1 H, m), 1.98-1.89 (1 H, m), 1.32 (3 H, t) 27 ¹H NMR (400MHz, CDCl₃) δ ppm 7.86 (2 H, dd), 7.49 (1 H, d), 7.22-7.04 (4 H, m),6.67 (1 H, s), 5.89-5.75 (1 H, m)NH, 4.53-4.40 (1 H, m), 3.86-3.68 (1 H,m), 3.67-3.51 (5 H, m), 3.47-3.35 (1 H, m), 3.23-3.13 (2 H, m), 3.07 (4H, bs), 2.78-2.65 (6 H, m), 2.34-2.10 (1 H, m), 2.00-1.95 (3 H, m),1.93-1.77 (1 H, m), 1.33 (3 H, t) 28 ¹H NMR (400 MHz, MeOD-d₄) δ ppm7.90 (2 H, dd), 7.45 (1 H, d), 7.40-7.29 (2 H, m), 7.12 (2 H, t), 6.95(1 H, d), 5.44-5.36 (0.5 H, m), 5.31-5.22 (0.5 H, m), 4.66-4.51 (1 H,m), 4.42-4.22 (2 H, m), 4.10-3.96 (1 H, m), 3.61 (3 H, s), 3.20-3.03 (6H, m), 2.77-2.61 (6 H, m), 1.31 (3 H, t) 30 ¹H NMR (400 MHz, MeOD-d₄) δppm 7.97-7.84 (2 H, m), 7.44 (1 H, d), 7.39-7.30 (2 H, m), 7.15-7.07 (2H, m), 6.93 (1 H, s), 4.27 (2 H, t), 4.00 (2 H, s), 3.60 (3 H, s),3.16-3.03 (6 H, m), 2.74-2.60 (6 H, m), 2.28 (2 H, q), 1.30 (3 H, t) 31¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.01-7.80 (2 H, m), 7.44 (1 H, d),7.39-7.30 (2 H, m), 7.14-7.07 (2 H, m), 6.96-6.91 (1 H, m), 3.60 (3 H,s), 3.52 (2 H, t), 3.41 (2 H, t), 3.23 (2 H, bs), 3.17-3.05 (4 H, m),2.74-2.67 (6 H, m), 1.95 (2 H, quin), 1.85 (2 H, quin), 1.30 (3 H, t) 32¹H NMR (400 MHz, CDCl₃) δ ppm 7.86 (2 H, dd), 7.54 (1 H, d), 7.20-7.03(4 H, m), 6.68 (1 H, s), 3.71-3.57 (11 H, m), 3.24 (2 H, s), 3.07 (4 H,d), 2.78-2.64 (6 H, m), 1.34 (3 H, t) 33 ¹H NMR (300 MHz, MeOD-d₄) δ ppm7.96-7.83 (2 H, m), 7.51-7.28 (3 H, m), 7.19-7.05 (2 H, m), 6.95 (1 H,s), 3.61 (3 H, s), 3.13 (4 H, d), 3.05 (2 H, s), 2.76-2.64 (6 H, m),1.31 (3 H, t) 34 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.92-7.79 (2 H, m), 7.56(1 H, d), 7.22-7.15 (2 H, m), 7.10 (2 H, t), 6.69 (1 H, s), 4.29 (1 H,t), 4.13-4.01 (2 H, m), 3.85-3.72 (3 H, m), 3.61 (3 H, s), 3.08 (6 H,s), 2.85-2.63 (7 H, m), 1.34 (3 H, t) 35 ¹H NMR (400 MHz, CDCl₃) δ ppm7.87 (2 H, dd), 7.49 (1 H, d), 7.20-7.06 (4 H, m), 6.67 (1 H, s), 3.61(3 H, s), 3.23 (2 H, s), 3.13-3.02 (7 H, m), 2.95 (3 H, s), 2.77-2.66 (6H, m), 1.33 (3 H, t) 36 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.86 (2 H, dd),7.50 (1 H, d), 7.20-7.04 (4 H, m), 6.67 (1 H, s), 4.19 (2 H, d), 3.61 (3H, s), 3.27 (2 H, s), 3.10 (4 H, m), 2.79-2.68 (6 H, m), 1.33 (3 H, t),1.28 (3 H, t) 37 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.86 (2 H, dd), 7.49 (1H, d), 7.19-7.05 (4 H, m), 6.67 (1 H, s), 4.18 (2 H, dd), 3.60 (3 H, s),3.33 (1 H, q), 3.12-2.96 (4 H, m), 2.83-2.66 (6 H, m), 1.37-1.24 (9 H,m) 38 ¹H NMR (400 MHz, MeOD-d₄) δ ppm 7.90-7.85 (2 H, m), 7.45 (1 H, d),7.35 (1 H, dd), 7.32 (1 H, d), 7.09 (2 H, t), 6.90 (1 H, s), 3.67 (2 H,s), 3.59 (3 H, s), 3.04-2.15 (4 H, m), 2.70 (4 H, bt), 2.67 (2 H, q),1.29 (3 H, t) 39 ¹H NMR (400 MHz, MeOD-d₄) δ ppm 7.89-7.84 (2 H, m),7.44 (1 H, d), 7.36 (1 H, dd), 7.31 (1 H, d), 7.13-7.09 (2 H, m), 6.91(1 H, s), 3.97 (2 H, s), 2.85 (1 H, sept), 3.59 (3 H, s), 3.33-3.29 (4H, m), 3.14-3.03 (4 H, m), 2.70-2.65 (6 H, m), 1.29 (3 H, t) 40 ¹H NMR(400 MHz, MeOD-d₄) δ ppm 7.92-7.85 (3 H, m), 7.44 (1 H, dd), 7.38-7.29(2 H, m), 7.15 (1 H, d), 7.11 (2 H, t), 6.93 (1 H, s), 3.77 (2 H, s),3.59 (3 H, s), 3.16-3.02 (4 H, m), 2.73-2.63 (6 H, m), 1.30 (3 H, t) 41¹H NMR (400 MHz, CDCl₃) δ ppm 8.70 (1 H, bs), 7.86-7.81 (2 H, m), 7.67(1 H, d), 7.23 (1 H, dd), 7.17 (1 H, d), 7.11-7.06 (2 H, m), 6.69 (1 H,s), 3.83 (2 H, s), 3.59 (3 H, s), 3.15-3.04 (4 H, m), 2.79-2.71 (6 H,m), 1.35 (3 H, t) 42 ¹H NMR (400 MHz, MeOD-d₄) δ ppm 7.93-7.86 (2 H, m),7.45 (1 H, dd), 7.41-7.35 (2 H, m), 7.11 (2 H, t), 6.95 (1 H, s), 3.61(3 H, s), 3.25-3.13 (6 H, m), 2.96-2.89 (4 H, m), 2.70 (2 H, q), 1.31 (3H, t) 43 ¹H NMR (400 MHz, MeOD-d₄) δ ppm 7.89 (2 H, dd), 7.50-7.34 (3 H,m), 7.16-7.05 (2 H, m), 6.94 (1 H, s), 4.17-4.10 (2 H, m), 3.74-3.67 (2H, m), 3.68-3.57 (7 H, m), 3.14-2.98 (4 H, m), 2.69 (2 H, q), 1.30 (3 H,t) 44 ¹H NMR (400 MHz, CDCl₃) δ ppm (2 conformers) 7.86 (2 H, dd),7.57-7.47 (1 H, m), 7.19 (1 H, s), 7.16-7.02 (3 H, m), 6.67 (1 H, s),4.67 (0.5 H, dd), 4.54 (0.5 H, d), 3.77 (3 H, bs), 3.70-3.33 (6 H, m),3.18-2.89 (4 H, m), 2.72 (2 H, q), 2.28-1.93 (2 H, m), 1.92-1.77 (2 H,m), 1.49-1.29 (12 H, m) 45 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.84 (2 H, dd),7.51 (1 H, d), 7.19 (1 H, s), 7.15-7.02 (3 H, m), 6.66 (1 H, s),3.88-3.62 (4 H, m), 3.59 (3 H, s), 3.51 (3 H, bs), 3.32 (1 H, bs), 3.18(1 H, bs), 3.02 (4 H, bs), 2.71 (2 H, q), 2.39-2.53 (0.5 H, m),2.18-2.33 (0.5 H, m), 2.14-1.94 (1 H, m), 1.43 (9 H, s), 1.32 (3 H, t)46 ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.08 (1 H, dd), 7.92-7.85 (3 H, m),7.78 (1 H, s), 7.21 (1 H, s), 7.15 (2 H, t), 4.81-4.76 (1 H, m),3.91-3.75 (4 H, m), 3.72 (3 H, s), 3.50-3.29 (6 H, m), 2.94 (2 H, q),2.64-2.53 (1 H, m), 2.21-1.93 (3 H, m), 1.44 (3H, t) 47 ¹H NMR (400 MHz,MeOD-d₄) δ ppm 8.09-8.05 (1 H, m), 7.94-7.85 (3 H, m), 7.75 (1 H, sb),7.21 (1 H, s), 7.15 (2 H, t), 3.86-3.52 (9 H, m), 3.49-3.26 (7 H, m),2.94 (2 H, q), 2.48-2.28 (1 H, m), 2.18-2.07 (1 H, m), 1.44 (3 H, t) 48¹H NMR (400 MHz, CDCl₃) δ ppm 7.90-7.86 (2 H, m), 7.73-7.66 (1 H, m),7.25-7.25 (2 H, m), 7.16-7.11 (2 H, m), 6.73 (1 H, s), 3.88-3.76 (2 H,m), 3.76-3.61 (6 H, m), 3.60-3.18 (4 H, m), 3.16-3.02 (4 H, m), 2.80 (2H, q), 2.50-2.40 (1 H, m), 2.20-2.04 (4 H, m), 1.39 (3H, t) 49 ¹H NMR(400 MHz, CDCl₃) δ ppm 7.90-7.82 (2 H, m), 7.59 (1 H, d), 7.22 (1 H, d),7.16 (1 H, dd), 7.10 (2 H, t), 6.69 (1 H, s), 3.83-3.75 (2 H, m),3.71-3.65 (2 H, m), 3.61 (3 H, s), 3.60-3.55 (2 H, m), 3.55-3.46 (1 H,m), 3.38-3.29 (2 H, m), 3.11-3.00 (4 H, m), 2.91 (3 H, s), 2.75 (2 H,q), 2.29-2.09 (2 H, m), 1.35 (3 H, t) 50 ¹H NMR (400 MHz, MeOD-d₄) δ ppm7.88 (2 H, dd), 7.47 (1 H, dd), 7.42-7.34 (2 H, m), 7.11 (2 H, t), 6.93(1 H, s), 4.23 (2 H, s), 3.73 (2 H, bt), 3.60 (3 H, s), 3.54 (2 H, bt),3.14-2.99 (4 H, m), 2.69 (2 H, q), 1.30 (3 H, t) 51 ¹H NMR (400 MHz,MeOD-d₄) δ ppm 7.88 (2 H, dd), 7.50-7.44 (1 H, m), 7.42-7.32 (2 H, m),7.10 (2 H, t), 6.92 (1 H, s), 3.71 (2 H, s), 3.65 (2 H, t), 3.60 (3 H,s), 3.12-2.96 (4 H, m), 2.68 (2 H, q), 2.40 (2 H, q), 1.29 (3 H, t),1.10 (3 H, t) 52 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.86-7.82 (2 H, m), 7.51(1 H, d), 7.18 (1 H, d), 7.13-7.05 (3 H, m), 6.66 (1 H, s), 3.76 (2 H,t), 3.67 (2 H, t), 3.62 (2 H, t), 3.58 (3 H, s), 3.04-2.95 (4 H, m),2.70 (2 H, q), 2.50 (2 H, t), 1.90 (2 H, quint), 1.31 (3 H, t) 53 ¹H NMR(400 MHz, CDCl₃) δ ppm 7.92-7.82 (2 H, m), 7.52 (1 H, d), 7.20 (1 H, d),7.15-7.04 (3 H, m), 6.67 (1 H, s), 3.77 (2 H, t), 3.67-3.58 (5 H, m),3.06-2.94 (4 H, m), 2.73 (2 H, q), 2.40 (2 H, t), 2.33 (2 H, t), 2.22 (6H, s), 1.82 (2 H, quin), 1.33 (3 H, t) 54 ¹H NMR (400 MHz, CDCl₃) δ ppm7.85 (2 H, dd), 7.63 (1 H, d), 7.25 (1 H, s), 7.18 (1 H, bd), 7.09 (2 H,t), 6.70 (1 H, s), 3.62 (3 H, s), 3.44-3.34 (4 H, m), 3.21-3.10 (4 H,m), 2.83 (3 H, s), 2.76 (2 H, q), 1.35 (3 H, t) 55 ¹H NMR (400 MHz,MeOD-d₄) δ ppm 7.91-7.87 (2 H, m), 7.47 (1 H, d), 7.40-7.36 (2 H, m),7.14-7.08 (2 H, m), 6.94 (1 H, s), 3.69 (2 H, t), 3.60 (3 H, s), 3.42 (4H, bt), 3.21-3.11 (6 H, m), 2.69 (2 H, q), 2.26-2.19 (2 H, m), 1.30 (3H, t) 56 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.91-7.83 (2 H, m), 7.53 (1 H,d), 7.23 (1 H, d), 7.14-7.06 (3 H, m), 6.68 (1 H, s), 3.62 (3 H, s),3.46 (4 H, t), 3.16-3.05 (6 H, m), 2.74 (2 H, d), 2.70-2.57 (2H, m),2.37 (6 H, bs), 2.19-2.08 (2H, m), 1.34 (3 H, t) 57 ¹H NMR (400 MHz,CDCl₃) δ ppm 7.87 (2 H, dd), 7.52 (1 H, d), 7.23 (1 H, d), 7.15-7.06 (3H, m), 6.68 (1 H, s), 3.61 (3 H, s), 3.45 (4 H, bt), 3.17-3.03 (6 H, m),2.73 (2 H, q), 2.69-2.53 (6 H, m), 2.12-2.00 (2 H, m), 1.82 (4 H, bs),1.34 (3 H, t) 58 ¹H NMR (400 MHz, MeOD-d₄) δ ppm 7.88 (2 H, dd), 7.47 (1H, dd), 7.42-7.31 (2 H, m), 7.10 (2 H, t), 6.92 (1 H, s), 3.64 (2 H, t),3.60 (3 H, s), 3.40 (4 H, bt), 3.22-3.06 (6 H, m), 2.69 (2 H, q),2.03-1.90 (2 H, m), 1.30 (3 H, t) 59 ¹H NMR (400 MHz, MeOD-d₄) δ ppm7.90 (2 H, dd), 7.48 (1 H, dd), 7.44-7.34 (2 H, m), 7.12 (2 H, t), 6.95(1 H, s), 3.76 (3 H, s), 3.61 (3 H, s), 3.48 (4 H, bt), 3.23-3.08 (4 H,m), 2.70 (2 H, q), 1.31 (3 H, t) 60 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.95(1 H, d), 7.81-7.78 (2 H, m), 7.28 (1 H, d), 7.21-7.22 (1 H, m),7.09-7.04 (2 H, m), 6.71 (1 H, s), 4.01 (2 H, s), 3.58 (7 H, s), 3.58 (4H, m), 2.77 (2 H, q), 1.32 (3 H, t) 61 ¹H NMR (400 MHz, CDCl₃) δ ppm7.88-7.85 (2 H, m), 7.62 (1 H, d), 7.23 (1 H, d), 7.17-7.07 (3 H, m),6.70 (1 H, s), 6.51 (1 H, bs)NH, 5.68 (1 H, bs)NH, 2.90 (2 H, s), 3.61(3 H, s), 3.56-3.51 (4 H, m), 3.18-3.06 (4 H, m), 2.75 (2 H, q), 1.34 (3H, t) 62 ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.27 (1 H, d), 7.91-7.81 (2 H,m), 7.59 (1 H, dd), 7.39 (1 H, dd), 7.09 (2 H, t), 6.92 (1 H, s), 4.18(2 H, bs), 3.81-3.67 (4 H, m), 3.60 (3 H, s), 2.73 (2 H, q), 1.47 (9 H,s), 1.32 (3 H, t) 63 ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.29 (1 H, dd),7.84 (2 H, d), 7.60 (1 H, dd), 7.45-7.33 (3 H, m), 7.03 (1 H, s), 4.19(2 H, s), 3.83-3.70 (4 H, m), 3.61 (3 H, s), 2.74 (2 H, q), 1.48 (9 H,s), 1.33 (3 H, t) 64 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.89-7.86 (3 H, m),7.66 (2 H, d), 7.25-7.22 (1 H, m), 7.14-7.10 (2 H, m), 4.27-4.21 (2 H,m), 3.82-3.66 (2 H, m), 3.64 (3 H, s), 3.54 (2 H, s), 3.39 (2 H, s),3.07-3.04 (2 H, m), 2.79 (2 H, q), 1.37 (3 H, t), 1.32 (3 H, t) 65 ¹HNMR (400 MHz, MeOD-d₄) δ ppm 8.36 (1 H, dd), 7.94 (2 H, dd), 7.67 (1 H,dd), 7.46 (1 H, dd), 7.16 (2 H, t), 7.05-6.90 (1 H, m), 4.11 (2 H, s),3.89 (2 H, dd), 3.75-3.61 (5 H, m), 3.03 (3 H, s), 2.81 (2 H, q), 1.39(3 H, t) 66 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.86 (2 H, dd), 7.73 (1 H, s),7.61 (1 H, d), 7.37 (1 H, dd), 7.10 (2 H, t), 6.69 (1 H, s), 6.10 (1 H,bs), 3.97 (2 H, bs), 3.63 (3 H, s), 3.57-3.45 (2 H, m), 2.86 (3 H, s),2.77 (2 H, q), 2.61 (2 H, bs), 1.36 (3 H, t) 67 ¹H NMR (400 MHz,MeOD-d₄) δ ppm 7.95 (1 H, s), 7.91-7.86 (2 H, m), 7.61 (1 H, dd), 7.54(1 H, dd), 7.14-7.08 (2 H, m), 6.96 (1 H, s), 6.24-6.22 (1 H, m), 4.83(2 H, s), 4.13-4.09 (2 H, m), 3.66 (2 H, td), 3.63 (3 H, s), 2.73 (2 H,q), 2.66-2.53 (2 H, m), 1.32 (3 H, t) 68 ¹H NMR (300 MHz, CDCl₃) δ ppm7.82 (2 H, d), 7.73 (1 H, d), 7.62 (1 H, s), 7.47 (1 H, d), 7.38 (2 H,d), 6.77 (1 H, s), 6.22 (1 H, bs), 4.55-4.31 (4 H, m), 3.63 (3 H, s),2.90 (3 H, s), 2.79 (2 H, q), 1.37 (3 H, t) 69 ¹H NMR (400 MHz, CDCl₃) δppm 7.81 (2 H, d), 7.77-7.72 (2 H, m), 7.45-7.34 (3 H, m), 6.79 (1 H,s), 6.30-6.20 (1 H, m), 4.12-4.04 (2 H, m), 3.64 (3 H, s), 3.50-3.36 (2H, m), 2.87 (3 H, s), 2.80 (2 H, q), 2.53-2.45 (2 H, m), 1.39 (3 H, t)70 ¹H NMR (300 MHz, CDCl₃) δ ppm 7.84-7.77 (2 H, m), 7.73 (1 H, bs),7.58 (1 H, dd), 7.43 (2 H, d), 7.34 (1 H, dd), 6.70 (1 H, s), 6.16-6.05(1 H, m), 3.96 (2 H, bd), 3.63 (3 H, s), 3.55-3.45 (2 H, m), 2.85 (3 H,s), 2.76 (2 H, q), 2.64-2.55 (2 H, m), 1.39-1.32 (12 H, t) 71 ¹H NMR(400 MHz, CDCl₃) δ ppm 8.20 (1 H, bd), 7.87 (1 H, s), 7.78 (1 H, bd),7.73 (2 H, d), 6.92 (2 H, d), 6.72 (1 H, s), 6.20 (1 H, bs), 3.97 (2 H,bs), 3.83 (3 H, s), 3.64 (3 H, bs), 3.54-3.46 (2 H, m), 2.92 (2 H, q),2.84 (3 H, s), 2.60 (2 H, bs), 1.46 (3 H, t) 72 ¹H NMR (400 MHz, CDCl₃)δ ppm 7.94-7.87 (2 H, m), 7.72 (1 H, bs), 7.59 (1 H, d), 7.37 (1 H, dd),7.26 (2 H, bd), 6.76 (1 H, s), 6.10 (1 H, m), 3.97 (2 H, bs), 3.63 (3 H,s), 3.55-3.44 (2 H, m), 2.85 (3 H, s), 2.76 (2 H, q), 2.60 (2 H, bs),1.36 (3 H, t) 73 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.72 (2 H, s), 7.62-7.54(2 H, m), 7.35 (1 H, dd), 7.19 (1 H, q), 6.71 (1 H, s), 6.13-6.06 (1 H,m), 3.96 (2 H, d), 3.62 (3 H, s), 3.58-3.43 (2 H, m), 2.85 (3 H, s),2.75 (2 H, q), 2.61 (2 H, bs), 1.35 (3 H, t) 74 ¹H NMR (400 MHz,MeOD-d₄) δ ppm 7.93 (1 H, s), 7.91-7.82 (2 H, m), 7.63-7.48 (2 H, m),7.09 (2 H, t), 6.93 (1 H, s), 6.21 (1 H, t), 4.13 (2 H, t), 4.00-3.93 (2H, m), 3.62 (3 H, s), 3.50 (2 H, bt), 3.17-3.06 (2 H, m), 2.71 (2 H, q),2.64-2.47 (2 H, m), 2.13-2.03 (2 H, m), 1.99 (3 H, s), 1.31 (3 H, t) 75¹H NMR (400 MHz, MeOD-d₄) δ ppm 7.92 (1 H, s), 7.87 (2 H, dd), 7.61-7.47(2 H, m), 7.09 (2 H, t), 6.92 (1 H, s), 6.25-6.17 (1 H, m), 3.98-3.93 (2H, m), 3.66-3.58 (5 H, m), 3.49 (2 H, t), 3.18-3.04 (2 H, m), 2.71 (2 H,q), 2.64-2.47 (2 H, m), 2.03-1.90 (2 H, m), 1.31 (3 H, t) 76 ¹H NMR (400MHz, CDCl₃) δ ppm 7.81 (2 H, d), 7.77 (1 H, bs), 7.61 (1 H, d), 7.37 (2H, d), 7.29 (1 H, d), 6.76 (1 H, s), 5.90 (1 H, t), 3.79 (2 H, bs), 3.63(3 H, s), 3.26-3.20 (2 H, m), 3.15-3.07 (2 H, m), 2.77 (2 H, q), 1.35 (3H, t) 77 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.93-7.84 (2 H, m), 7.74 (1 H,s), 7.67 (1 H, dd), 7.40 (1 H, dd), 7.17-7.09 (2 H, m), 6.17-6.08 (1 H,m), 3.98 (2 H, bs), 3.46-3.59 (5 H, m), 2.86 (3 H, s), 2.77 (2 H, q),2.58-2.68 (2 H, m), 1.36 (3 H, t) 78 ¹H NMR (400 MHz, MeOD-d₄) δ ppm8.04 (1 H, d), 7.96-7.92 (2 H, m), 7.65-7.61 (1 H, m), 7.57-7.54 (1 H,m), 7.10 (2 H, t), 7.03 (1 H, s), 4.37-4.33 (1 H, m), 4.19-4.16 (1 H,m), 3.75-3.61 (4 H, m), 2.91-2.78 (3 H, m), 2.73-2.60 (2 H, m),1.91-1.66 (2 H, m), 1.52 (9 H, d), 1.39 (3H, t) 79 ¹H NMR (400 MHz,MeOD-d₄) δ ppm 8.00-7.79 (3 H, m), 7.55 (1 H, d), 7.48-7.41 (1 H, m),7.12 (2 H, t), 6.95 (1 H, d), 3.96-3.87 (1 H, m), 3.85-3.72 (2 H, m),3.63 (3 H, d), 2.87 (3 H, s), 2.85-2.77 (1 H, m), 2.73 (2 H, q),2.63-2.52 (2 H, m), 1.97-1.89 (2 H, m), 1.32 (3 H, t) 80 ¹H NMR (300MHz, CDCl₃) δ ppm 7.87 (2 H, dd), 7.67-7.53 (2 H, m), 7.21-7.05 (3 H,m), 6.69 (1 H, s), 3.95 (2 H, d), 3.63 (3 H, s), 2.82-2.70 (7 H, m),2.68-2.55 (1 H, m), 2.04-1.74 (4 H, m), 1.35 (3 H, t) 81 ¹H NMR (400MHz, CDCl₃) δ ppm 7.80 (2 H, d), 7.63 (1 H, bs), 7.58 (1 H, d), 7.43 (2H, d), 7.15 (1 H, dd), 6.70 (1 H, s), 3.99-3.90 (2 H, m), 3.62 (3 H, s),2.81 (3 H, s), 2.79-2.69 (4 H, m), 2.66-2.55 (1 H, m), 1.96 (2 H, d),1.90-1.75 (2 H, m), 1.35 (9 H, s), 1.26 (3 H, t) 82 ¹H NMR (300 MHz,CDCl₃) δ ppm 7.82 (2 H, d), 7.70-7.52 (2 H, m), 7.16 (1 H, dd), 6.95 (2H, d), 6.62 (1 H, s), 3.94 (2 H, d), 3.86 (3 H, s), 3.63 (3 H, s),2.84-2.69 (7 H, m), 2.68-2.58 (1 H, m), 2.02-1.92 (2 H, m), 1.92-1.74 (2H, m), 1.35 (3 H, t) 83 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.73 (1 H, ddd),7.63-7.53 (3 H, m), 7.24-7.11 (2 H, m), 6.70 (1 H, s), 3.95 (2 H, d),3.62 (3 H, s), 2.81 (3 H, s), 2.79-2.69 (4 H, m), 2.68-2.56 (1 H, m),2.01-1.92 (2 H, m), 1.82 (2 H, qd), 1.35 (3 H, t) 84 ¹H NMR (400 MHz,CDCl₃) δ ppm 8.00 (2 H, d), 7.71-7.56 (4 H, m), 7.17 (1 H, dd), 6.88 (1H, s), 3.95 (2 H, d), 3.64 (3 H, s), 2.81 (3 H, s), 2.80-2.71 (4 H, m),2.68-2.57 (1 H, m), 1.97 (2 H, d), 1.85 (2 H, qd), 1.36 (3 H, t) 85 ¹HNMR (400 MHz, CDCl₃-d) δ ppm 7.91 (2 H, d), 7.62 (1 H, s), 7.59 (1 H,d), 7.26 (2 H, d), 7.16 (1 H, dd), 6.75 (1 H, s), 3.95 (2 H, d), 3.63 (3H, s), 2.81 (3 H, s), 2.79-2.70 (4 H, m), 2.68-2.57 (1 H, m), 2.01-1.92(2 H, m), 1.90-1.74 (2 H, m), 1.35 (3 H, t) 86 ¹H NMR (400 MHz, MeOD-d₄)δ ppm 7.95-7.83 (3 H, m), 7.52 (1 H, dd), 7.39 (1 H, dd), 7.19-7.04 (2H, m), 6.94 (1 H, s), 3.85 (2 H, bd), 3.70 (2 H, t), 3.62 (3 H, s),3.23-3.14 (2 H, m), 2.93 (2 H, bt), 2.83-2.66 (3 H, m), 2.27-2.14 (2 H,m), 1.90 (2 H, bd), 1.77 (2 H, qd), 1.32 (3 H, t) 87 ¹H NMR (400 MHz,CDCl₃) δ ppm 7.91-7.82 (2 H, m), 7.61 (1 H, s), 7.57 (1 H, d), 7.19-7.06(3 H, m), 6.68 (1 H, s), 3.94 (2 H, d), 3.62 (3 H, s), 3.05-2.96 (2 H,m), 2.85 (2 H, t), 2.75 (2 H, q), 2.66-2.55 (1 H, m), 2.41 (2 H, t),2.24 (6 H, s), 2.05-1.88 (4 H, m), 1.86-1.71 (2 H, m), 1.34 (3 H, t) 88¹H NMR (400 MHz, MeOD-d₄) δ ppm 7.92-7.84 (3 H, m), 7.53 (1 H, d), 7.39(1 H, dd), 7.11 (2 H, t), 6.93 (1 H, s), 3.84 (2 H, d), 3.68 (4 H, t),3.62 (3 H, s), 3.08 (2 H, t), 2.91 (2 H, t), 2.81-2.66 (3 H, m),2.52-2.38 (6 H, m), 2.01-1.85 (4 H, m), 1.75 (2 H, q), 1.31 (3 H, t) 89¹H NMR (400 MHz, MeOD-d₄) δ ppm 7.94-7.82 (3 H, m), 7.53 (1 H, d), 7.40(1 H, dd), 7.11 (2 H, t), 6.94 (1 H, s), 3.85 (2 H, d), 3.62 (3 H, s),3.08 (2 H, t), 2.92 (2 H, t), 2.82-2.68 (3 H, m), 2.67-2.55 (6 H, m),2.05-1.88 (4 H, m), 1.86-1.71 (6 H, m), 1.32 (3 H, t) 90 ¹H NMR (300MHz, CDCl₃) δ ppm 7.85 (2 H, dd), 7.61 (1 H, s), 7.57 (1 H, d),7.19-7.02 (3 H, m), 6.67 (1 H, s), 3.92 (2 H, bd), 3.61 (3 H, s),3.16-3.02 (1 H, m), 3.01-2.69 (7 H, m), 2.68-2.51 (1 H, m), 2.11-1.97 (2H, m), 1.96-1.87 (2 H, m), 1.86-1.66 (2 H, m), 1.34 (3 H, t) 91 ¹H NMR(400 MHz, MeOD-d₄) δ ppm 7.99-7.81 (3 H, m), 7.51 (2 H, dd), 7.10 (2 H,t), 6.96 (1 H, s), 3.84 (2 H, d), 3.75-3.58 (7 H, m), 3.24 (2 H, t),2.95 (2 H, t), 2.89-2.66 (5 H, m), 2.55 (4 H, bs), 1.92 (2 H, d),1.85-1.67 (2 H, m), 1.32 (3 H, t) 92 ¹H NMR (400 MHz, MeOD-d₄) δ ppm7.93-7.84 (3 H, m), 7.53 (1 H, dd), 7.40 (1 H, dd), 7.11 (2 H, t), 6.94(1 H, s), 3.75 (2 H, d), 3.62 (3 H, s), 2.76-2.66 (5 H, m), 1.90 (2 H,bd), 1.83 (2 H, qd), 1.32 (3 H, t) 93 ¹H NMR (400 MHz, MeOD-d₄) δ ppm7.91-7.82 (3 H, m), 7.52 (1 H, d), 7.38 (1 H, dd), 7.10 (2 H, t), 6.92(1 H, s), 4.15 (2 H, t), 3.83 (2 H, d), 3.61 (3 H, s), 3.14-3.05 (2 H,m), 2.96-2.86 (2 H, m), 2.77-2.64 (3 H, m), 2.15-2.04 (2 H, m), 2.02 (3H, s), 1.95-1.85 (2 H, m), 1.75 (2 H, dd), 1.31 (3 H, t) 94 ¹H NMR (400MHz, MeOD-d₄) δ ppm 7.96-7.81 (3 H, m), 7.53 (1 H, d), 7.41 (1 H, dd),7.11 (2 H, t), 6.95 (1 H, s), 3.85 (2 H, d), 3.65 (2 H, t), 3.62 (3 H,s), 3.13-3.07 (2 H, m), 2.93 (2 H, bt), 2.82-2.68 (3 H, m), 2.03-1.87 (4H, m), 1.85-1.70 (2 H, m), 1.32 (3 H, t) 95 ¹H NMR (400 MHz, CDCl₃) δppm 7.89 (2 H, dd), 7.63 (1 H, s), 7.59 (1 H, d), 7.18 (1 H, dd), 7.13(2 H, t), 4.00-3.92 (2 H, m), 3.80 (2 H, t), 3.52 (3 H, s), 3.12-3.06 (2H, m), 2.93-2.84 (2 H, m), 2.75 (2 H, q), 2.71-2.60 (1 H, m), 2.14-2.03(2 H, m), 2.00-1.89 (2 H, m), 1.88-1.74 (2 H, m), 1.36 (3 H, t) 96 ¹HNMR (400 MHz, MeOD-d₄) δ ppm 8.05 (1 H, dd), 7.92 (1 H, s), 7.61 (1 H,dd), 7.56-7.47 (2 H, m), 7.43 (1 H, dd), 7.27 (1 H, s), 3.84 (2 H, d),3.64 (3 H, s), 2.91-2.68 (8 H, m), 2.00-1.93 (2 H, m), 1.89-1.76 (2 H,m), 1.33 (3 H, t) 97 ¹H NMR (300 MHz, CDCl₃) δ ppm 7.69-7.58 (3 H, m),7.47 (1 H, dd), 7.38 (1 H, td), 7.20 (1 H, d), 3.97 (2 H, d), 3.53 (3 H,s), 2.89-2.61 (8 H, m), 2.24 (3 H, s), 2.07-1.94 (2 H, m), 1.93-1.77 (2H, m), 1.38 (3 H, t) 98 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.71-7.62 (2 H,m), 7.58 (1 H, d), 7.15 (1 H, dd), 7.01-6.91 (2 H, m), 6.48 (1 H, s),3.97 (2 H, d), 3.58 (3 H, s), 2.83 (3 H, s), 2.81-2.72 (4 H, m),2.72-2.61 (1 H, m), 2.53 (3 H, s), 2.04-1.94 (2 H, m), 1.91-1.82 (2 H,m), 1.36 (3 H, t) 99 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.08 (1 H, dd), 7.63(1 H, bs), 7.60 (1 H, d), 7.19 (2 H, ddd), 7.11 (1 H, s), 7.10-7.05 (1H, m), 3.96 (2 H, d), 3.60 (3 H, s), 2.82 (3 H, s), 2.81-2.70 (4 H, m),2.68-2.58 (1 H, m), 2.03-1.93 (2 H, m), 1.93-1.76 (2 H, m), 1.36 (3 H,t) 100 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.29-8.18 (1 H, m), 7.66-7.56 (2 H,m), 7.16 (1 H, dd), 7.03-6.95 (2 H, m), 6.89 (1 H, ddd), 3.95 (2 H, d),3.62 (3 H, s), 2.82 (3 H, s), 2.82-2.71 (4 H, m), 2.66-2.57 (1 H, m),2.01-1.94 (2 H, m), 1.88-1.81 (2 H, m), 1.35 (3 H, t) 101 ¹H NMR (400MHz, CDCl₃) δ ppm 7.71-7.61 (3 H, m), 7.57 (1 H, d), 7.18-7.05 (3 H, m),3.96 (2 H, d), 3.54 (3 H, s), 2.88-2.71 (7 H, m), 2.69-2.56 (1 H, m),2.32 (3 H, s), 2.04-1.93 (2 H, m), 1.92-1.77 (2 H, m), 1.36 (3 H, t) 102¹H NMR (400 MHz, CDCl₃) δ ppm 7.87 (2 H, dd), 7.62 (1 H, s), 7.59 (1 H,d), 7.15 (1 H, dd), 7.11 (2 H, t), 6.68 (1 H, s), 3.95 (2 H, d), 2.82 (3H, s), 2.80-2.70 (4 H, m), 2.68-2.55 (1 H, m), 2.03-1.91 (2 H, m),1.91-1.76 (2 H, m), 1.35 (3 H, t) 103 ¹H NMR (400 MHz, CDCl₃) δ ppm7.89-7.76 (3 H, m), 7.66 (1 H, s), 7.28 (1 H, dd), 7.10 (2 H, t), 3.95(2 H, d), 2.83-2.71 (7 H, m), 2.69-2.60 (1 H, m), 2.00-1.93 (2 H, m),1.90-1.76 (2 H, m), 1.34 (3 H, t) 104 ¹H NMR (400 MHz, CDCl₃) δ ppm7.93-7.83 (2 H, m), 7.63-7.53 (2 H, m), 7.22-7.05 (3 H, m), 3.97 (2 H,bd), 3.67 (3 H, s), 3.60 (3 H, s), 2.83 (3 H, s), 2.82-2.72 (4 H, m),2.70-2.59 (1 H, m), 2.04-1.93 (2 H, m), 1.92-1.78 (2 H, m), 1.37 (3 H,t) 105 ¹H NMR (400 MHz, MeOD-d₄) δ ppm 7.96 (1 H, s), 7.69-7.60 (2 H,m), 7.55 (1 H, d), 7.44 (1 H, dd), 7.23 (2 H, t), 3.85 (2 H, d), 3.59 (3H, s), 2.91-2.81 (5 H, m), 2.80-2.68 (3 H, m), 2.00 (3 H, s), 1.99-1.92(2 H, m), 1.91-1.77 (2 H, m), 1.33 (3 H, t) 106 ¹H NMR (400 MHz, CDCl₃)δ ppm 11.56 (1 H, bs), 8.43 (1 H, d), 7.66 (1 H, d), 7.61 (1 H, s), 7.55(1 H, dd), 7.22 (1 H, d), 6.84-6.73 (2 H, m), 3.96 (2 H, d), 3.63 (3 H,s), 2.87-2.71 (7 H, m), 2.71-2.54 (1 H, m), 2.09 (3 H, s), 2.02-1.92 (2H, m), 1.91-1.77 (2 H, m), 1.37 (3 H, t) 107 ¹H NMR (300 MHz, CDCl₃) δppm 7.61 (2 H, dd), 7.53 (1 H, dd), 7.17 (2 H, td), 7.05 (1 H, td), 6.64(1 H, s), 4.60 (2 H, d), 3.97 (2 H, d), 3.58 (3 H, s), 2.87-2.59 (8 H,m), 2.05-1.76 (4 H, m), 1.36 (3 H, t) 108 ¹H NMR (400 MHz, MeOD-d₄) δppm 7.92-7.82 (3 H, m), 7.61 (1 H, dd), 7.51 (1 H, d), 7.10 (2 H, t),6.94 (1 H, s), 6.20 (1 H, bs), 4.18 (2 H, q), 3.62 (3 H, s), 3.39 (2 H,s), 3.36-3.32 (2 H, m), 2.86 (2 H, bt), 2.72 (2 H, q), 2.61-2.49 (2 H,m), 1.31 (3 H, t), 1.26 (3 H, t) 109 ¹H NMR (400 MHz, MeOD-d₄) δ ppm7.88 (2 H, dd), 7.83 (1 H, s), 7.50 (1 H, dd), 7.39 (1 H, dd), 7.14-7.07(2 H, m), 6.93 (1 H, s), 4.17 (2 H, q), 3.61 (3 H, s), 3.24 (2 H, s),3.07-3.00 (2 H, m), 2.71 (2 H, q), 2.66-2.54 (1 H, m), 2.38-2.22 (2 H,m), 1.87-1.74 (4 H, m), 1.31 (3 H, t), 1.26 (3 H, t) 110 ¹H NMR (400MHz, CDCl₃) δ ppm 7.90-7.81 (2 H, m), 7.61 (1 H, bs), 7.55 (1 H, d),7.20 (1 H, dd), 7.13-7.06 (2 H, m), 6.67 (1 H, s), 4.72-4.65 (1 H, m),4.49-4.42 (1 H, m), 4.31-4.24 (1 H, m), 4.11 (1 H, dd), 3.90 (1 H, dd),3.61 (3 H, s), 3.10-2.99 (4 H, m), 2.73 (2 H, q), 2.56-2.45 (1 H, m),2.28-2.17 (2 H, m), 1.94-1.76 (4 H, m), 1.34 (3 H, t) 111 ¹H NMR (400MHz, CDCl₃) δ ppm 7.93-7.83 (2 H, m), 7.61 (1 H, s), 7.54 (1 H, d), 7.18(1 H, d), 7.10 (2 H, t), 6.67 (1 H, s), 4.59-4.45 (1 H, m), 3.72-3.50 (7H, m), 3.18 (1 H, d), 3.14 (1 H, s), 3.01-3.11 (2 H, m), 2.74 (2 H, q),2.57-2.47 (1 H, m), 2.27-2.17 (2 H, m), 1.86-1.70 (6 H, m), 1.34 (3 H,t) 112 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.87 (2 H, dd), 7.61 (1 H, s), 7.54(1 H, d), 7.18 (1 H, dt), 7.10 (2 H, t), 6.67 (1 H, s), 4.59-4.48 (1 H,m), 3.72-3.50 (7 H, m), 3.21-3.13 (2 H, m), 3.13-3.01 (2 H, m), 2.75 (2H, q), 2.56-2.44 (1 H, m), 2.28-2.18 (2 H, m), 2.09-1.93 (2 H, m), 1.82(4 H, m), 1.34 (3 H, t) 113 ¹H NMR (300 MHz, CDCl₃) δ ppm 7.87 (2 H,dd), 7.61 (1 H, s), 7.55 (1 H, d), 7.18 (1 H, dd), 7.10 (2 H, t), 6.68(1 H, s), 4.31 (1 H, t), 4.14-4.00 (2 H, m), 3.86-3.74 (3 H, m), 3.62 (3H, s), 3.09-2.98 (4 H, m), 2.78 (3 H, m), 2.60-2.44 (1 H, m), 2.27-2.14(2 H, m), 1.89-1.78 (4 H, m), 1.35 (3 H, t) 114 ¹H NMR (300 MHz, CDCl₃)δ ppm 7.87 (2 H, dd), 7.61 (1 H, s), 7.54 (1 H, dd), 7.18 (1 H, dd),7.10 (2 H, t), 6.67 (1 H, s), 3.61 (3 H, s), 3.19 (2 H, s), 3.12-2.99 (5H, m), 2.95 (3 H, s), 2.74 (2 H, q), 2.57-2.42 (1 H, m), 2.29-2.11 (2 H,m), 1.87-1.74 (4 H, m), 1.34 (3 H, t) 115 ¹H NMR (400 MHz, CDCl₃) δ ppm7.91-7.83 (2 H, m), 7.61 (1 H, bs), 7.54 (1 H, d), 7.18 (1 H, dd), 7.10(2 H, t), 6.67 (1 H, s), 3.61 (3 H, s), 3.49 (4 H, q), 3.15 (2 H, s),3.07 (2 H, bd), 2.75 (2 H, q), 2.55-2.44 (1 H, m), 2.28-2.17 (2 H, m),1.94 (2 H, q), 1.89-1.77 (6 H, m), 1.34 (3 H, t) 116 ¹H NMR (400 MHz,CDCl₃) δ ppm 7.87 (2 H, dd), 7.61 (1 H, s), 7.55 (1 H, d), 7.22-7.15 (1H, m), 7.11 (2 H, t), 6.68 (1 H, s), 3.93 (1 H, d), 3.84-3.66 (3 H, m),3.62 (3 H, s), 3.22-3.08 (3 H, m), 3.08-2.94 (2 H, m), 2.75 (2 H, q),2.57-2.44 (1 H, m), 2.34 (1 H, q), 2.31-2.12 (3 H, m), 1.89-1.76 (4 H,m), 1.35 (3 H, t) 117 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.91-7.88 (2 H, m),7.64 (1 H, bs), 7.57 (1 H, d), 7.23-7.20 (1 H, m), 7.13 (2 H, t), 6.70(1 H, s), 3.73-3.61 (7 H, m), 3.57-3.40 (2 H, m), 3.31-3.08 (4 H, m),2.78 (2 H, q), 2.57-2.34 (2 H, m), 2.29-2.17 (2 H, m), 1.91-2.04 (1 H,m), 1.90-1.80 (4 H, m), 1.72-1.62 (1 H, m), 1.37 (3H, t) 118 ¹H NMR (400MHz, CDCl₃) δ ppm 7.86 (2 H, dd), 7.60 (1 H, s), 7.54 (1 H, d), 7.17 (1H, dd), 7.09 (2 H, t), 6.67 (1 H, s), 4.85-4.77 (1 H, m), 4.52 (1 H, t),4.23 (1 H, dd), 3.61 (3 H, s), 3.00 (2 H, t), 2.78-2.67 (4 H, m),2.53-2.43 (1 H, m), 2.36-2.19 (2 H, m), 1.87-1.79 (2 H, m), 1.79-1.66 (2H, m), 1.33 (3 H, t) 119 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.87 (2 H, dd),7.62 (1 H, s), 7.55 (1 H, d), 7.19 (1 H, d), 7.10 (2 H, t), 6.67 (1 H,s), 3.82-3.73 (2 H, m), 3.61 (3 H, s), 3.58-3.51 (2 H, m), 3.25 (2 H,s), 3.18-3.05 (2 H, m), 2.98 (3 H, s), 2.74 (2 H, q), 2.60-2.49 (1 H,m), 2.34-2.21 (2 H, m), 1.87-1.79 (2 H, m), 1.79-1.66 (2 H, m), 1.34 (3H, t) 120 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.87 (2 H, dd), 7.61 (1 H, s),7.54 (1 H, d), 7.19 (1 H, dd), 7.10 (2 H, t), 6.67 (1 H, s), 3.71 (3 H,s), 3.61 (3 H, s), 3.35 (2 H, s), 3.19 (3 H, s), 3.11 (2 H, bd), 2.75 (2H, q), 2.56-2.44 (1 H, m), 2.32-2.19 (2 H, m), 1.80-1.72 (4 H, m), 1.34(3 H, t) 121 ¹H NMR (400 MHz, CDCl₃) δ ppm (2 conformers) 7.87 (2 H,dd), 7.62 (1 H, s), 7.55 (1 H, d), 7.23-7.15 (1 H, m), 7.11 (2 H, t),6.68 (1 H, s), 4.62 (0.7 H, s), 4.35 (1.3 H, s), 3.62 (3 H, s),3.31-3.20 (4 H, m), 3.06 (1 H, s), 3.04-2.87 (2 H, m), 2.75 (2 H, q),2.57-2.45 (1 H, m), 2.30-2.14 (2 H, m), 1.93-1.74 (4 H, m), 1.35 (3 H,t) 122 ¹H NMR (300 MHz, CDCl₃) δ ppm 7.85 (2 H, dd), 7.66-7.48 (2 H, m),7.22-6.99 (3 H, m), 6.66 (1 H, s), 6.11 (1 H, s)NH, 4.84-4.69 (1 H, m),3.73-3.52 (4 H, m), 3.42-3.26 (1 H, m), 3.09 (1 H, d), 2.96 (1 H, d),2.80-2.66 (3 H, m), 2.65-2.57 (1 H, m), 2.56-2.40 (1 H, m), 2.34-2.08 (2H, m), 1.93-1.64 (4 H, m), 1.32 (3 H, t) 123 ¹H NMR (400 MHz, CDCl₃) δppm 7.90-7.82 (2 H, m), 7.62 (1 H, s), 7.57 (1 H, d), 7.18 (1 H, dd),7.15-7.06 (2 H, m), 6.68 (1 H, s), 3.66-3.57 (5 H, m), 3.47 (2 H, q),3.07 (2 H, s), 2.99-2.90 (3 H, m), 2.81-2.68 (3 H, m), 2.57-2.48 (1 H,m), 2.30 (2 H, t), 1.93-1.82 (2 H, m), 1.78-1.66 (2 H, m), 1.39-1.29 (5H, m) 124 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.87-7.84 (2 H, m), 7.60 (1 H,bs), 7.54 (1 H, d), 7.16 (1 H, dd), 7.09 (2 H, t), 6.66 (1 H, s), 4.58(2 H, t), 4.33 (2 H, t), 3.60 (3 H, s), 3.12 (2 H, s), 2.97 (2 H, bd),2.74 (2 H, q), 2.53-2.45 (1 H, m), 2.17 (2 H, bt), 1.85-1.69 (4 H, m),1.32 (3 H, t) 125 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.90-7.84 (2 H, m), 7.62(1 H, s), 7.56 (1 H, d), 7.17 (1 H, dd), 7.14-7.07 (2 H, m), 7.06-7.02(1 H, bs)NH, 6.68 (1 H, s), 5.44-5.34 (1 H, bs)NH, 3.63 (3 H, s),3.06-2.96 (4 H, m), 2.76 (2 H, q), 2.57-2.47 (1 H, m), 2.28 (2 H, bt),1.92-1.84 (2 H, m), 1.81-1.69 (2 H, m), 1.35 (3 H, t) 126 ¹H NMR (400MHz, CDCl₃) δ ppm 7.87 (2 H, dd), 7.64-7.52 (2 H, m), 7.17-7.05 (3 H,m), 6.68 (1 H, s), 4.76 (1 H, d), 4.21 (1 H, d), 3.62 (3 H, s),3.50-3.25 (2 H, m), 3.08 (1 H, t), 2.82-2.69 (3 H, m), 2.69-2.51 (5 H,m), 1.90 (2 H, d), 1.85-1.73 (4 H, m), 1.60 (2 H, quin), 1.35 (3 H, t)127 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.90-7.82 (2 H, m), 7.60 (1 H, s),7.56 (1 H, d), 7.18-7.05 (3 H, m), 6.67 (1 H, s), 4.78 (1 H, d), 3.88 (1H, d), 3.62 (3 H, s), 3.43 (2 H, d), 3.09 (1 H, bt), 2.82-2.71 (3 H, m),2.66 (1 H, bt), 2.46 (3 H, s), 1.91 (2 H, d), 1.71-1.54 (2 H, m), 1.34(3 H, t) 128 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.93-7.78 (2 H, m), 7.67-7.51(2 H, m), 7.20-7.03 (3 H, m), 6.68 (1 H, s), 4.72 (1 H, d), 4.55-4.36 (1H, m), 3.94 (1 H, d), 3.85-3.70 (2 H, m), 3.62 (3 H, s), 3.49-3.28 (2 H,m), 3.22-3.00 (2 H, m), 2.85-2.68 (3 H, m), 2.67-2.25 (2 H, m), 1.89 (2H, d), 1.76-1.46 (2 H, m), 1.34 (3 H, t) 129 ¹H NMR (300 MHz, CDCl₃) δppm 7.85 (2 H, dd), 7.64-7.50 (2 H, m), 7.17-7.02 (3 H, m), 6.67 (1 H,s), 4.74 (1 H, d), 4.23 (1 H, d), 3.61 (3 H, s), 3.22-2.98 (3 H, m),2.82-2.69 (3 H, m), 2.60 (1 H, t), 2.29 (6 H, s), 1.89 (2 H, d),1.73-1.45 (2 H, m), 1.33 (3 H, t) 130 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.86(2 H, dd), 7.60 (1 H, s), 7.55 (1 H, d), 7.17-7.04 (3 H, m), 6.67 (1 H,s), 4.82-4.72 (1 H, m), 3.99 (1 H, d), 3.61 (3 H, s), 3.12 (1 H, t),2.84-2.68 (5 H, m), 2.67-2.56 (3 H, m), 2.36 (6 H, s), 1.90 (2 H, t),1.68-1.51 (2 H, m), 1.33 (3 H, t) 131 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.86(2 H, dd), 7.62-7.55 (2 H, m), 7.15-7.05 (3 H, m), 6.68 (1 H, s), 4.72(1 H, d), 3.92 (1 H, d), 3.74 (4 H, t), 3.62 (3 H, s), 3.47 (2 H, q),3.10 (1 H, bt), 2.75 (3 H, q), 2.62 (1 H, bt), 1.91 (2 H, d), 1.70-1.51(2 H, m), 1.34 (3 H, t) 132 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.85 (2 H,dd), 7.60 (1 H, s), 7.55 (1 H, d), 7.17-7.02 (3 H, m), 6.67 (1 H, s),4.76 (1 H, d), 3.96 (1 H, d), 3.61 (3 H, s), 3.24 (1 H, bs)NH, 3.11 (1H, t), 2.92 (2 H, t), 2.80-2.71 (3 H, m), 2.69-2.61 (3 H, m), 2.49 (3 H,s), 1.96-1.82 (2 H, m), 1.69-1.50 (2 H, m), 1.33 (3 H, t) 133 ¹H NMR(400 MHz, CDCl₃) δ ppm 7.90-7.82 (2 H, m), 7.62-7.56 (2 H, m), 7.17-7.06(3 H, m), 6.68 (1 H, s), 5.24 (0.5 H, quin), 5.09 (0.5 H, quin), 4.73 (1H, d), 4.01-3.76 (3 H, m), 3.62 (3 H, s), 3.42 (2 H, q), 3.33 (1 H, dd),3.27 (1 H, dd), 3.10 (1 H, t), 2.82-2.69 (3 H, m), 2.61 (1 H, t), 1.90(2 H, d), 1.74-1.50 (2 H, m), 1.35 (3 H, t) 134 ¹H NMR (400 MHz, CDCl₃)δ ppm 7.85 (2 H, dd), 7.65-7.58 (2 H, m), 7.23 (1 H, d), 7.10 (2 H, t),6.68 (1 H, s), 4.13 (1 H, t), 4.07-3.96 (2 H, m), 3.87 (1 H, dd), 3.61(3 H, s), 3.20-3.10 (1 H, m), 3.01-2.88 (2 H, m), 2.76 (2 H, q),2.63-2.51 (1 H, m), 2.04-1.84 (7 H, m), 1.77 (2 H, t), 1.35 (3 H, t) 135¹H NMR (400 MHz, CDCl₃) δ ppm 8.50-8.43 (1 H, m), 7.93-7.87 (2 H, m),7.85 (1 H, s), 7.83-7.76 (1 H, m), 7.12 (2 H, t), 4.00 (2 H, bd), 3.61(3 H, s), 2.99 (2 H, q), 2.88-2.78 (6 H, m), 2.09-1.99 (2 H, m),1.93-1.79 (2 H, m), 1.54 (3 H, t) 136 ¹H NMR (300 MHz, CDCl₃) δ ppm8.23-8.12 (2 H, m), 7.68-7.53 (2 H, m), 7.25-7.13 (3 H, m), 3.98 (2 H,d), 3.65 (3 H, s), 2.89-2.70 (8 H, m), 2.10-1.94 (2 H, m), 1.94-1.77 (2H, m), 1.38 (3 H, t) 137 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.10 (1 H, s),7.75 (2 H, t), 7.54 (1 H, d), 7.36 (1 H, d), 7.25 (2 H, t), 3.68 (2 H,d), 3.50 (3 H, s), 3.30 (2 H, s)NH2, 2.89 (3 H, s), 2.82-2.71 (3 H, m),2.63 (2 H, q), 1.92-1.83 (2 H, m), 1.81-1.71 (2 H, m), 1.25 (3 H, t) 138¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.16 (2 H, dd), 7.58-7.36 (3 H, m), 7.26(2 H, t), 4.61-4.53 (1 H, m), 4.54-4.42 (1 H, m), 4.21 (1 H, dd), 4.05(1 H, dd), 3.77 (1 H, dd), 3.66 (3 H, s), 3.20-3.09 (6 H, m), 2.76-2.62(6 H, m), 1.33 (3 H, t) 139 ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.16 (2 H,dd), 7.51-7.38 (3 H, m), 7.26 (2 H, t), 4.37-4.28 (1 H, m), 4.09-3.99 (2H, m), 3.81-3.72 (1 H, m), 3.70-3.63 (5 H, m), 3.15 (4 H, d), 3.11 (2 H,s), 2.83-2.64 (7 H, m), 1.33 (3 H, t) 140 ¹H NMR (300 MHz, CDCl₃) δ ppm8.22-8.10 (2 H, m), 7.52 (1 H, d), 7.23-7.14 (3 H, m), 7.10 (1 H, d),3.62 (3 H, s), 3.24 (2 H, d), 3.16-3.06 (7 H, m), 2.95 (3 H, s),2.79-2.65 (6 H, m), 1.35 (3 H, t) 141 ¹H NMR (400 MHz, CDCl₃) δ ppm8.22-8.12 (2 H, m), 7.63-7.54 (2 H, m), 7.24 (1 H, dd), 7.19 (2 H, t),4.74-4.66 (1 H, m), 4.49-4.42 (1 H, m), 4.29 (1 H, dd), 4.11 (1 H, dd),3.90 (1 H, dd), 3.64 (3 H, s), 3.08-2.99 (4 H, m), 2.75 (2 H, q),2.57-2.47 (1 H, m), 2.23-2.14 (2 H, m), 1.89-1.77 (4 H, m), 1.36 (3 H,t) 142 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.19-8.11 (2 H, m), 7.59-7.52 (2 H,m), 7.24 (1 H, d), 7.21-7.13 (2 H, m), 4.51 (1 H, dd), 3.71-3.57 (5 H,m), 3.56-3.46 (1 H, m), 3.19-3.00 (4 H, m), 2.73 (2 H, q), 2.57-2.46 (1H, m), 2.28-2.08 (4 H, m), 2.09-1.94 (1 H, m), 1.87-1.76 (4 H, m), 1.34(3 H, t) 142 ¹H NMR (400 MHz, MeOD-d₄) δ ppm 7.89 (2 H, dd), 7.48-7.42(1 H, m), 7.40-7.28 (2 H, m), 7.11 (2 H, t), 6.94 (1 H, s), 4.66 (2 H,t), 4.33 (2 H, t), 3.61 (3 H, s), 3.19 (2 H, s), 3.17-3.03 (4 H, m),2.74-2.61 (6 H, m), 1.30 (3 H, t) 143 ¹H NMR (400 MHz, MeOD-d₄) δ ppm8.15 (2 H, dd), 7.95 (1 H, s), 7.52 (2 H, dd), 7.25 (2 H, t), 4.39 (1 H,d), 3.67-3.58 (4 H, m), 3.57-3.41 (3 H, m), 3.23-3.14 (2 H, m),3.11-3.00 (2 H, m), 2.74 (2 H, q), 2.67-2.57 (1 H, m), 2.29-2.17 (2 H,m), 2.06-1.91 (2 H, m), 1.89-1.76 (4 H, m), 1.34 (3 H, t) 144 ¹H NMR(400 MHz, CDCl₃) δ ppm 8.22-8.12 (2 H, m), 7.64-7.53 (2 H, m), 7.27-7.23(1 H, m), 7.19 (2 H, t), 4.33-4.26 (1 H, m), 4.13-4.04 (2 H, m),3.86-3.77 (3 H, m), 3.64 (3 H, s), 3.16-3.07 (4 H, m), 2.87-2.80 (1 H,m), 2.75 (2 H, q), 2.64-2.55 (1 H, m), 2.47-2.34 (2 H, m), 1.90-1.84 (4H, m), 1.37 (3 H, t) 145 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.21-8.12 (2 H,m), 7.63-7.50 (2 H, m), 7.24 (1 H, dd), 7.18 (2 H, t), 3.63 (3 H, s),3.23 (2 H, s), 3.11-3.03 (5 H, m), 2.95 (3 H, s), 2.75 (2 H, q),2.60-2.49 (1 H, m), 2.34-2.22 (2 H, m), 1.90-1.80 (4 H, m), 1.36 (3 H,t) 146 ¹H NMR (400 MHz, MeOD-d₄) δ ppm 7.70 (2 H, dd), 7.47-7.41 (1 H,m), 7.40-7.30 (2 H, m), 7.17 (2 H, t), 4.56 (2 H, s), 4.32 (1 H, t),4.09-3.98 (2 H, m), 3.76 (1 H, dd), 3.67 (2 H, d), 3.55 (3 H, s),3.18-3.05 (6 H, m), 2.83-2.74 (1 H, m), 2.74-2.62 (6 H, m), 1.32 (3 H,t) 147 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.78-7.71 (2 H, m), 7.63 (1 H, s),7.59 (1 H, d), 7.21-7.10 (3 H, m), 4.69 (2 H, s), 3.96 (2 H, d), 3.57 (3H, s), 2.83 (3 H, s), 2.81-2.70 (4 H, m), 2.69-2.59 (1 H, m), 2.03-1.94(2 H, m), 1.91-1.77 (2 H, m), 1.34 (3 H, t) 148 ¹H NMR (300 MHz, CDCl₃)δ ppm 7.85-7.75 (2 H, m), 7.68-7.58 (2 H, m), 7.30 (2 H, dd), 7.20 (1 H,dd), 4.71 (2 H, s), 3.97 (2 H, d), 3.57 (3 H, s), 2.83 (3 H, s), 2.76 (4H, m), 2.71-2.57 (1 H, m), 1.99 (2 H, d), 1.85 (2 H, bq), 1.35 (3 H, t)149 ¹H NMR (300 MHz, CDCl₃) δ ppm 7.80-7.71 (2 H, m), 7.61 (1 H, bs),7.54 (1 H, d), 7.19-7.09 (3 H, m), 4.68 (2 H, s), 3.93 (2 H, d), 3.56 (3H, s), 3.06-2.97 (2 H, m), 2.94-2.81 (2 H, m), 2.77-2.58 (3 H, m), 2.44(2 H, t), 2.25 (6 H, s), 2.08-1.98 (4 H, m), 1.89-1.71 (2 H, m), 1.32 (3H, t) 150 ¹H NMR (300 MHz, CDCl₃) δ ppm 7.91 (2 H, d), 7.71 (2 H, d),7.63 (1 H, s), 7.55 (1 H, d), 7.16 (1 H, dd), 4.72 (2 H, s), 3.95 (2 H,d), 3.57 (3 H, s), 2.88-2.56 (8 H, m), 2.04-1.74 (4 H, m), 1.30 (3 H, t)151 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.76 (2 H, dd), 7.60 (1 H, s), 7.47 (1H, d), 7.19-7.08 (3 H, m), 4.66 (2 H, s), 3.53 (3 H, s), 3.46 (4 H, q),3.13 (2 H, s), 3.04 (2 H, bd), 2.71-2.60 (2 H, m), 2.54-2.44 (1 H, m),2.27-2.14 (2 H, m), 1.99-1.89 (2 H, m), 1.88-1.75 (6 H, m), 1.28 (3 H,t) 152 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.74 (2 H, dd), 7.60 (1 H, s), 7.48(1 H, d), 7.19-7.08 (3 H, m), 4.66 (2 H, s), 4.29-4.21 (1 H, m), 4.03 (2H, bt), 3.81-3.72 (3 H, m), 3.54 (3 H, s), 3.07-2.96 (4 H, m), 2.84-2.73(1 H, m), 2.68 (2 H, q), 2.56-2.43 (1 H, m), 2.28-2.13 (2 H, m), 1.80 (4H, bs.), 1.29 (3 H, t) 153 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.79-7.72 (2 H,m), 7.60 (1 H, s), 7.53 (1 H, d), 7.19-7.08 (3 H, m), 4.75 (1 H, d),4.68 (2 H, s), 4.25 (1 H, d), 3.56 (3 H, s), 3.24-3.03 (3 H, m),2.81-2.58 (4 H, m), 2.32 (6 H, s), 1.91 (2 H, d), 1.71-1.52 (2 H, m),1.33 (3 H, t) 154 ¹H NMR (300 MHz, CDCl₃) δ ppm 7.76 (2 H, dd), 7.60 (1H, s), 7.53 (1 H, d), 7.18-7.10 (3 H, m), 4.81 (1 H, d), 4.68 (2 H, s),3.99 (1 H, d), 3.56 (3 H, s), 3.12 (1 H, t), 2.82-2.54 (4 H, m), 2.38 (2H, q), 1.99-1.83 (2 H, m), 1.80-1.50 (2 H, m), 1.32 (3 H, t), 1.17 (3 H,t) 155 ¹H NMR (400 MHz, MeOD-d₄) δ ppm 7.78-7.64 (2 H, m), 7.43 (1 H,d), 7.40-7.32 (2 H, m), 7.17 (2 H, t), 4.56 (2 H, s), 3.55 (3 H, s),3.28 (2 H, s), 3.18-3.10 (4 H, m), 3.09 (3 H, s), 2.93 (3 H, s),2.74-2.65 (6 H, m), 1.31 (3 H, t) 156 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.74(2 H, dd), 7.60 (1 H, s), 7.52 (1 H, d), 7.21-7.09 (3 H, m), 4.73-4.65(3 H, m), 4.50-4.43 (1 H, m), 4.27 (1 H, dd), 4.10 (1 H, dd), 3.89 (1 H,dd), 3.56 (3 H, s), 3.05 (2 H, s), 3.01 (2 H, d), 2.74 (2 H, q),2.55-2.46 (1 H, m), 2.25-2.14 (2 H, m), 1.89-1.80 (2 H, m), 1.74-1.56 (2H, m), 1.34 (3 H, t) 157 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.75 (2 H, dd),7.61 (1 H, s), 7.53 (1 H, d), 7.22-7.11 (3 H, m), 4.67 (2 H, s), 3.56 (3H, s), 3.21 (2 H, s), 3.09 (3 H, s), 3.08-3.00 (2 H, m), 2.96 (3 H, s),2.74 (2 H, q), 2.58-2.46 (1 H, m), 2.27-2.17 (2 H, m), 1.89-1.79 (4 H,m), 1.35 (3 H, t) 158 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.79 (2 H, dd), 7.58(1 H, d), 7.22 (1 H, dd), 7.17-7.11 (3 H, m), 3.63 (3 H, s), 3.30 (2 H,d), 3.19-3.11 (4 H, m), 3.07 (3 H, s), 2.95 (3 H, s), 2.85-2.71 (6 H,m), 1.36 (3 H, t) 159 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.86-7.73 (2 H, m),7.67-7.53 (2 H, m), 7.26-7.24 (1 H, m), 7.15 (2 H, t), 4.73-4.65 (1 H,m), 4.49-4.40 (1 H, m), 4.29 (1 H, dd), 4.11 (1 H, dd), 3.92 (1 H, dd),3.64 (3 H, s), 3.13 (4 H, bs), 2.82-2.71 (2 H, m), 2.62-2.51 (1 H, m),2.39-2.24 (2 H, m), 1.88 (4 H, bs), 1.38 (3 H, t) 160 ¹H NMR (300 MHz,CDCl₃) δ ppm 7.84-7.75 (2 H, m), 7.67-7.57 (2 H, m), 7.23 (1 H, dd),7.15 (2 H, t), 4.03-3.93 (2 H, m), 3.65 (3 H, s), 2.85-2.72 (7 H, m),2.73-2.59 (1 H, m), 2.07-1.95 (2 H, m), 1.88 (2 H, qd), 1.38 (3 H, t)161 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.63-7.59 (1 H, m), 7.51-7.44 (2 H,m), 7.40-7.33 (1 H, m), 7.21 (1 H, d), 7.11 (1 H, dd), 3.51 (3 H, s),3.13 (8 H, bs), 2.75 (2 H, q), 2.22 (3 H, s), 1.35 (3 H, t) 162 ¹H NMR(300 MHz, CDCl₃) δ ppm 7.62 (1 H, dd), 7.54 (1 H, d), 7.46 (1 H, dd),7.42-7.33 (1 H, m), 7.19 (2 H, s), 4.68 (1 H, bs), 4.52-4.41 (1 H, m),4.29 (1 H, dd), 4.13 (1 H, dd), 3.91 (1 H, dd), 3.52 (3 H, s), 3.17-3.02(6 H, m), 2.82-2.64 (6 H, m), 2.24 (3 H, s), 1.37 (3 H, t) 163 ¹H NMR(300 MHz, CDCl₃) δ ppm 7.61 (2 H, dd), 7.47 (1 H, dd), 7.33-7.43 (1 H,m), 7.05-7.24 (2 H, m), 3.53 (3 H, s), 3.04-3.18 (6 H, m), 2.86 (3 H,d), 2.64-2.83 (6 H, m), 2.24 (3 H, s), 1.39 (3 H, t) 164 ¹H NMR (300MHz, CDCl₃) δ ppm 8.05 (1 H, dd), 7.62 (1 H, d), 7.45 (1 H, dd), 7.38 (1H, m), 7.16-7.25 (3 H, m), 5.36-5.45 (0.5 H, m), 5.18-5.25 (0.5 H, m),4.45-4.61 (1 H, m), 4.24-4.44 (2 H, m), 4.05-4.23 (1 H, m), 3.62 (3 H,s), 3.05-3.17 (6 H, m), 2.64-2.82 (6 H, m), 1.37 (3 H, t) 165 ¹H NMR(300 MHz, CDCl₃) δ ppm 8.04 (1 H, dd), 7.65 (1 H, d), 7.45 (1 H, dd),7.37 (1 H, ddd), 7.26-7.16 (3 H, m), 4.58 (2 H, t), 4.36 (2 H, t), 3.62(3 H, s), 3.19 (2 H, s), 3.16-3.07 (4 H, m), 2.78 (2 H, q), 2.72-2.63 (4H, m), 1.38 (3 H, t) 166 ¹H NMR (300 MHz, CDCl₃) δ ppm 8.07 (1 H, dd),7.57-7.32 (3 H, m), 7.22-7.09 (3 H, m), 4.77-4.62 (1 H, m), 4.46 (1 H,t), 4.28 (1 H, dd), 4.11 (1 H, dd), 3.90 (1 H, dd), 3.61 (3 H, s),3.18-3.03 (6 H, m), 2.82-2.61 (6 H, m), 1.34 (3 H, t) 167 ¹H NMR (400MHz, CDCl₃) δ ppm 8.06 (1 H, dd), 7.62 (1 H, d), 7.45 (1 H, dd),7.41-7.34 (1 H, m), 7.25-7.16 (3 H, m), 4.24 (2 H, t), 4.06 (2 H, t),3.61 (3 H, s), 3.18-3.05 (6 H, m), 2.81-2.67 (6 H, m), 2.29 (2 H, quin),1.37 (3 H, t) 168 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.07 (1 H, dd), 7.59 (1H, d), 7.44 (1 H, dd), 7.37 (1 H, dd), 7.24-7.15 (3 H, m), 3.61 (3 H,s), 3.26 (2 H, s), 3.18-3.03 (7 H, m), 2.95 (3 H, s), 2.81-2.68 (6 H,m), 1.35 (3 H, t) 169 ¹H NMR (300 MHz, CDCl₃) δ ppm 8.03 (1 H, dd), 7.68(1 H, d), 7.45 (1 H, dd), 7.38 (1 H, dd), 7.22-7.17 (2 H, m), 7.11-7.01(1 H, m), 3.62 (3 H, s), 3.17-3.07 (6 H, m), 2.85 (3 H, d), 2.79 (2 H,q), 2.76-2.68 (4 H, m), 1.38 (3 H, t) 170 ¹H NMR (400 MHz, CDCl₃) δ ppm8.09 (1 H, dd), 7.61 (1 H, s), 7.54 (1 H, d), 7.45 (1 H, dd), 7.41-7.34(1 H, m), 7.23-7.16 (2 H, m), 4.74-4.65 (1 H, m), 4.51-4.41 (1 H, m),4.36-4.23 (1 H, m), 4.19-4.07 (1 H, m), 3.98-3.83 (1 H, m), 3.62 (3 H,s), 3.10-2.96 (4 H, m), 2.76 (2 H, q), 2.60-2.44 (1 H, m), 2.27-2.15 (2H, m), 1.84 (4 H, bs), 1.35 (3 H, t) 171 ¹H NMR (300 MHz, MeOD-d₄) δ ppm8.10-8.01 (1 H, m), 7.90 (1 H, s), 7.63 (1 H, dd), 7.56-7.46 (2 H, m),7.42 (1 H, dd), 7.30 (1 H, s), 3.64 (3 H, s), 3.26 (2 H, s), 3.10 (3 H,s), 3.09-2.99 (2 H, m), 2.94 (3 H, s), 2.74 (2 H, q), 2.68-2.57 (1 H,m), 2.30-2.18 (2 H, m), 1.90-1.79 (4 H, m), 1.33 (3 H, t) 172 ¹H NMR(400 MHz, MeOD-d₄) δ ppm 7.86 (1 H, s), 7.70-7.64 (2 H, m), 7.56-7.48 (2H, m), 7.43-7.38 (1 H, m), 4.62-4.55 (1 H, m), 4.54-4.47 (1 H, m), 4.22(1 H, dd), 4.07 (1 H, ddd), 3.78 (1 H, dd), 3.53 (3 H, s), 3.10 (2 H,s), 3.02 (2 H, bd), 2.74 (2 H, q), 2.69-2.58 (1 H, m), 2.28-2.19 (5 H,m), 1.90-1.79 (4 H, m), 1.34 (3 H, t) 173 ¹H NMR (400 MHz, CDCl₃) δ ppm8.36 (1 H, dd), 7.62-7.55 (2 H, m), 7.52 (1 H, dd), 7.43-7.35 (1 H, m),7.23 (1 H, dd), 4.73-4.64 (1 H, m), 4.51-4.42 (1 H, m), 4.29 (1 H, dd),4.12 (1 H, dd), 3.90 (1 H, dd), 3.71 (3 H, s), 3.11-3.01 (4 H, m), 2.75(2 H, q), 2.58-2.48 (1 H, m), 2.29-2.18 (2 H, m), 1.92-1.78 (4 H, m),1.35 (3 H, t) 174 ¹H NMR (400 MHz, DMSO) δ ppm 8.04 (1 H, s), 7.96-7.90(2 H, m), 7.61-7.55 (1 H, m), 7.37 (1 H, dd), 7.28-7.20 (3 H, m), 3.58(3 H, s), 3.14 (2 H, s), 3.01 (3 H, s), 2.91 (6 H, bs), 2.79 (3 H, s),2.60-2.54 (1 H, m), 2.12-2.05 (2 H, m), 1.73-1.62 (4 H, m) 175 ¹H NMR(400 MHz, CDCl₃) δ ppm 7.71 (2 H, dd), 7.64 (1 H, s), 7.56 (1 H, d),7.21 (1 H, dd), 7.14 (2 H, t), 4.68 (2 H, bd), 3.96 (2 H, bd), 3.09-3.05(2 H, m), 2.98-2.91 (1 H, m), 2.89-2.73 (6H, m), 2.68-2.61 (1 H, m),2.28-2.16 (1 H, bs), 2.01-1.95 (2 H, m), 1.91-1.78 (2 H, m) 176 ¹H NMR(400 MHz, DMSO-d) δ ppm 7.99 (1 H, s), 7.96-7.91 (2 H, m), 7.50 (1 H,d), 7.36 (1 H, bs)NH, 7.32 (1 H, d), 7.27-7.21 (3 H, m), 6.78 (1 H,bs)NH, 3.55 (3 H, s), 3.10 (2 H, s), 3.01 (3 H, s), 2.90 (2 H, d),2.87-2.65 (5 H, m), 2.60-2.42 (3 H, m), 2.12-2.04 (2 H, m), 1.75-1.60(4H, m) 177 ¹H NMR (300 MHz, CDCl₃) δ ppm 7.92-7.83 (2 H, m), 7.48 (1 H,d), 7.15-7.04 (2 H, m), 6.86 (1 H, d), 6.73 (1 H, dd), 6.68 (1 H, s),4.12 (2 H, t), 4.01-3.90 (1 H, m), 3.60 (3 H, s), 3.41 (2 H, q), 2.72 (2H, q), 1.78 (2 H, bs)NH2, 1.34 (3 H, t) 178 ¹H NMR (400 MHz, CDCl₃) δppm 7.86 (2 H, dd), 7.45 (1 H, d), 7.10 (2 H, t), 6.85 (1 H, d), 6.73 (1H, dd), 6.67 (1 H, s), 4.76-4.64 (1 H, m), 4.33-4.21 (2 H, m), 4.03 (2H, bt), 3.98 (1 H, dd), 3.90 (1 H, dd), 3.80-3.69 (1 H, m), 3.59 (3 H,s), 3.56-3.45 (2 H, m), 3.20 (2 H, s), 2.71 (2 H, q), 1.32 (3 H, t) 179¹H NMR (400 MHz, CDCl₃) δ ppm 7.87 (2 H, dd), 7.49 (1 H, d), 7.42 (1 H,d)NH, 7.10 (2 H, t), 6.88 (1 H, d), 6.72 (1 H, dd), 6.68 (1 H, s), 4.86(1 H, d), 4.46 (1 H, t), 4.19 (2 H, td), 3.71 (2 H, dd), 3.66-3.54 (5 H,m), 3.17 (2 H, s), 3.14-3.04 (2 H, m), 2.73 (2 H, q), 1.34 (3 H, t) 180¹H NMR (400 MHz, CDCl₃) δ ppm 7.86 (2 H, dd), 7.50 (1 H, d), 7.18 (1 H,s), 7.17-7.06 (3 H, m), 6.67 (1 H, s), 3.67-3.62 (2 H, m), 3.61 (3 H,s), 3.09-3.04 (4 H, m), 2.77-2.57 (8 H, m), 1.33 (3 H, t) 181 ¹H NMR(400 MHz, MeOD-d₄) δ ppm 7.90 (2 H, dd), 7.47 (1 H, d), 7.42-7.29 (2 H,m), 7.12 (2 H, t), 6.95 (1 H, s), 3.81 (4 H, bt), 3.61 (3 H, s),3.12-2.94 (4 H, m), 2.70 (2 H, q), 1.31 (3 H, t) 182 ¹H NMR (400 MHz,MeOD-d₄) δ ppm 7.94-7.85 (2 H, m), 7.56 (1 H, dd), 7.49 (1 H, dd), 7.40(1 H, dd), 7.11 (2 H, t), 6.95 (1 H, s), 3.71-3.64 (4 H, m), 3.62 (3 H,s), 3.22-3.16 (4 H, m), 2.71 (2 H, q), 1.31 (3 H, t) 183 ¹H NMR (400MHz, MeOD-d₄) δ ppm 8.31-8.28 (1 H, m), 7.88-7.84 (2 H, m), 7.72 (1(Gen- H, dd), 7.54 (1 H, dd), 7.41-7.35 (2 H, m), 7.02 (1 H, s),3.98-3.93 (2 H, m), 3.62 (3 H, 10- s), 3.56-3.52 (2 H, m), 2.72 (2 H,q), 1.32 (3H, t) a) 184 ¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.39-8.28 (1 H,m), 7.84 (2 H, d), 7.71 (1 H, dd), 7.57 (1 H, dd), 7.40-7.33 (2 H, m),7.00 (1 H, s), 4.18 (2 H, q), 4.01 (2 H, s), 3.93-3.86 (2 H, m),3.67-3.57 (5 H, m), 2.72 (2 H, q), 1.31 (3 H, t), 1.25 (3 H, t) 185 ¹HNMR (400 MHz, CDCl₃) δ ppm 7.83-7.72 (4 H, m), 7.51 (1 H, d), 7.38 (2 H,d), 6.81 (1 H, s), 6.19-6.09 (1 H, m), 3.98 (2 H, bd), 3.71-3.56 (5 H,m), 3.56-3.46 (2 H, m), 2.86 (3 H, s), 2.66-2.57 (2 H, m) 186 ¹H NMR(400 MHz, CDCl₃) δ ppm 7.64-7.57 (4 H, m), 7.22-7.14 (3 H, m), 3.97 (2H, d), 3.72 (2 H, d), 3.56 (3 H, s), 2.85-2.72 (7 H, m), 2.71-2.60 (1 H,m), 2.06-1.95 (2 H, m), 1.86 (2 H, qd), 1.37 (3 H, t) 187 ¹H NMR (300MHz, CDCl₃) δ ppm 8.41 (1 H, d), 8.05-7.90 (2 H, m), 7.65-7.42 (2 H, m),7.28 (1 H, dd), 7.13 (3 H, d), 6.03 (1 H, t), 4.00-3.87 (2 H, m), 3.62(3 H, s), 3.47 (2 H, t), 2.82 (3 H, s), 2.73 (2 H, q), 2.64-2.43 (2 H,m), 1.28 (3 H, t) 188 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.18 (2 H, d), 7.58(1 H, d), 7.43 (2 H, d), 7.23-7.13 (2 H, m), 3.67 (3 H, s), 3.44-3.36 (4H, m), 3.22-3.09 (4 H, m), 2.83 (3 H, s), 2.74 (2 H, q), 1.35 (3 H, t)189 ¹H NMR (300 MHz, CDCl₃) δ ppm 8.01-7.97 (2 H, m), 7.67 (1 H, s),7.59 (1 H, d), 7.34 (1 H, dd), 7.14 (2 H, t), 6.10 (1 H, s), 3.98 (2 H,bs), 3.63 (3 H, s), 3.52 (2 H, q), 2.86 (3 H, s), 2.76 (2 H, d), 2.62 (2H, bs), 1.35 (3 H, t) 190 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.24 (2 H, dd),7.67 (1 H, s), 7.56 (1 H, d), 7.41 (1 H, dd), 7.14 (2 H, t), 6.08 (1 H,bs), 3.67 (3 H, s), 3.31 (2 H, s), 3.27 (2 H, bs), 3.08 (3 H, s), 2.95(3 H, s), 2.83-2.49 (4 H, m), 2.54-2.45 (2 H, m), 1.35 (3 H, t) 191 ¹HNMR (400 MHz, CDCl₃) δ ppm 8.28-8.20 (2 H, m), 7.61-7.53 (2 H, m), 7.21(1 H, dd), 7.14 (2 H, t), 3.67 (3 H, s), 3.19 (2 H, s), 3.08 (3 H, s),3.03 (2 H, bd), 2.95 (3 H, s), 2.74 (2 H, q), 2.56-2.42 (1 H, m),2.24-2.15 (2 H, m), 1.92-1.68 (4 H, m), 1.35 (3 H, t) 192 ¹H NMR (400MHz, CDCl₃) δ ppm 7.92-7.80 (2 H, m), 7.64 (1 H, s), 7.47 (1 H, d), 7.17(1 H, s), 7.13-7.05 (3 H, m), 7.01 (1 H, s), 6.66 (1 H, s), 3.66 (2 H,s), 3.59 (3 H, s), 3.08 (4 H, d), 2.77-2.65 (6 H, m), 1.32 (3 H, t) 193¹H NMR (400 MHz, CDCl₃) δ ppm 7.99 (2 H, d), 7.73 (1 H, s), 7.66 (2 H,d), 7.59 (1 H, dd), 7.35 (1 H, dd), 6.88 (1 H, s), 6.13-6.08 (1 H, m),3.96 (2 H, d), 3.64 (3 H, s), 3.56-3.43 (2 H, m), 2.85 (3 H, s), 2.76 (2H, q), 2.64-2.56 (2 H, m), 1.36 (3 H, t) 194 ¹H NMR (400 MHz, CDCl₃) δppm 7.87 (2 H, dd), 7.62 (1 H, s), 7.56 (1 H, d), 7.18 (1 H, dd), 7.11(2 H, t), 6.69 (1 H, s), 3.63 (3 H, s), 2.99 (2 H, s), 2.91 (2 H, d),2.82-2.68 (3 H, m), 2.57-2.45 (1 H, m), 2.24 (2 H, bt), 1.86 (2 H, d),1.77-1.66 (2 H, m), 1.35 (3 H, t), 0.85-0.74 (2 H, m), 0.57-0.48 (2 H,m) 195 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.90-7.84 (2 H, m), 7.61 (1 H, s),7.57 (1 H, d), 7.18 (1 H, dd), 7.10 (2 H, t), 6.67 (1 H, s), 4.71-4.61(1 H, m), 3.65-3.58 (4 H, m), 3.31-3.24 (1 H, t), 3.13 (1 H, bd), 3.00(1 H, bd), 2.88 (3 H, s), 2.75 (2 H, q), 2.68 (2 H, dd), 2.55-2.46 (1 H,m), 2.36-2.18 (2 H, m), 1.86-1.70 (4 H, m), 1.34 (3 H, t) 196 ¹H NMR(400 MHz, CDCl₃) δ ppm 7.87 (2 H, dd), 7.60 (1 H, s), 7.54 (1 H, d),7.17 (1 H, dd), 7.10 (2 H, t), 6.67 (1 H, s), 5.23-5.08 (1 H, m)NH, 4.79(1 H, quin), 3.67 (1 H, t), 3.61 (3 H, s), 3.37 (1 H, t), 3.09 (1 H,bd), 2.99 (1 H, bd), 2.79-2.69 (3 H, m), 2.68-2.60 (1 H, m), 2.54-2.43(1 H, m), 2.34-2.17 (2 H, m), 1.86-1.65 (4 H, m), 1.34 (3 H, t) 197 ¹HNMR (400 MHz, CDCl₃) δ ppm 7.86 (2 H, dd), 7.60 (1 H, s), 7.54 (1 H, d),7.16 (1 H, dd), 7.10 (2 H, t), 6.67 (1 H, s), 5.10-4.86 (1 H, m)NH, 4.79(1 H, quin), 3.67 (1 H, t), 3.61 (3 H, s), 3.37 (1 H, t), 3.09 (1 H,bs), 2.99 (1 H, bs), 2.79-2.60 (4 H, m), 2.55-2.42 (1 H, m), 2.34-2.17(2 H, m), 1.86-1.67 (4 H, m), 1.34 (3 H, t) 198 ¹H NMR (400 MHz,DMSO-d₆) δ ppm7.95-7.90 (3 H, m), 7.66 (1 H, s), 7.51 (1 H, d),7.31-7.20 (4 H, m), 4.34 (1 H, t), 4.01-3.97 (1 H, m), 3.96-3.88 (1 H,m), 3.54 (3 H, s), 2.96-2.88 (2 H, m), 2.63-2.38 (3 H, m), 2.38-2.35 (2H, m), 2.09-1.93 (2 H, m), 1.72-1.56 (4 H, m), 1.21 (3 H, t) 199 ¹H NMR(400 MHz, CDCl₃) δ ppm 8.28-8.19 (2 H, m), 7.77-7.68 (2 H, m), 7.46 (1H, dd), 7.14 (2 H, t), 6.15-6.08 (1 H, m), 4.01-3.95 (2 H, m), 3.69 (3H, s), 3.58-3.44 (2 H, m), 2.86 (3 H, s), 2.79 (2 H, q), 2.68-2.57 (2 H,m), 1.35 (3 H, t) 200 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.87-7.83 (2 H, m),7.54 (1 H, d), 7.21 (1 H, d), 7.13-7.06 (3 H, m), 6.67 (1 H, s), 3.78 (2H, t), 3.65 (2 H, t), 3.60 (3 H, s), 3.09-3.03 (4 H, m), 2.73 (2 H, q),2.43 (3 H, s), 1.33 (3 H, t) 201 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.85 (2H, dd), 7.53 (1 H, d), 7.22 (1 H, d), 7.15-7.01 (3 H, m), 6.67 (1 H, s),6.49 (1 H, d)NH, 4.48 (1 H, dd), 3.84-3.74 (2 H, m), 3.60 (5 H, bs),3.12-2.96 (4 H, m), 2.73 (2 H, q), 2.50-2.28 (3 H, m), 2.16-2.06 (1 H,m), 1.33 (3 H, t) 202 ¹H NMR (300 MHz, CDCl₃) δ ppm 7.86 (2 H, dd), 7.54(1 H, d), 7.24-7.04 (4 H, m), 6.68 (1 H, s), 3.84 (4 H, bt), 3.61 (3 H,s), 3.04 (4 H, bt), 2.73 (2 H, q), 1.33 (3 H, t), 1.07-0.99 (2 H, m),0.86-0.77 (2 H, m) 203 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.85 (2 H, dd),7.56 (1 H, d), 7.22 (1 H, d), 7.17-7.03 (3 H, m), 6.68 (1 H, s),4.52-4.43 (1 H, m), 3.93-3.70 (2 H, m), 3.66-3.51 (5 H, m), 3.13-2.97 (4H, m), 2.74 (2 H, q), 1.40-1.28 (6 H, m) 204 ¹H NMR (400 MHz, CDCl₃) δppm 7.87-7.81 (2 H, m), 7.53 (1 H, dd), 7.20 (1 H, d), 7.14-7.05 (3 H,m), 7.04 (1 H, bs) NH, 6.66 (1 H, s), 5.59 (1 H, bs) NH, 4.24 (2 H, t),3.80 (2 H, t), 3.59 (3 H, s), 2.72 (2 H, q), 3.11-3.05 (4 H, m), 1.33 (3H, t) 205 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.85 (2 H, dd), 7.54 (1 H, d),7.35-7.18 (6 H, m), 7.14-7.02 (3 H, m), 6.68 (1 H, s), 4.56 (1 H, d),4.35 (1 H, dd), 3.88-3.69 (2 H, m), 3.67-3.50 (6 H, m), 3.46-3.29 (2 H,m), 3.10-2.91 (4 H, m), 2.85-2.60 (4 H, m), 1.33 (3 H, t) 206 ¹H NMR(400 MHz, MeOD-d₄) δ ppm 8.33 (1 H, dd), 7.84-7.81 (2 H, m), 7.70 (1 H,dd), 7.58 (1 H, dd), 7.36-7.34 (2 H, m), 7.00 (1 H, s), 4.49-4.45 (2 H,m), 4.09-4.04 (2 H, m), 3.60 (3H, s), 2.72 (2 H, q), 1.32 (3 H, s) 207¹H NMR (400 MHz, MeOD-d₄) δ ppm 8.03 (1 H, dd), 7.85 (2 H, d), 7.56 (1H, dd), 7.46 (1 H, dd), 7.37 (2 H, d), 7.03 (1 H, s), 3.71-3.65 (2 H,m), 3.61 (3 H, s), 3.29-3.23 (2 H, m), 2.73 (2 H, q), 2.30-2.21 (2 H,m), 1.92-1.83 (2 H, m), 1.32 (3 H, t) 208 ¹H NMR (400 MHz, MeOD-d₄) δppm 7.92-7.84 (3 H, m), 7.61 (1 H, dd), 7.52 (1 H, d), 7.14-7.07 (2 H,m), 6.93 (1 H, s), 6.81-6.75 (2 H, m), 6.64-6.62 (1 H, m), 6.28-6.18 (1H, m), 4.16-4.14 (2 H, m), 3.70 (2 H, t), 3.62 (3 H, s), 2.72 (2 H, q),2.64-2.44 (2 H, m), 1.29 (3 H, t) 209 ¹H NMR (400 MHz, MeOD-d₄) δ ppm7.95 (1 H, s), 7.91-7.81 (2 H, m), 7.62 (1 H, dd), 7.54 (1 H, dd),7.42-7.33 (2 H, m), 7.04 (1 H, s), 6.25 (1 H, t), 3.95-3.91 (2 H, m),3.63 (3 H, s), 3.47 (2 H, td), 2.87 (3 H, s), 2.73 (2 H, q), 2.67-2.50(2 H, m), 1.32 (3 H, t) 210 ¹H NMR (400 MHz, MeOD-d₄) δ ppm 7.95 (1 H,s), 7.90-7.80 (2 H, m), 7.62 (1 H, dd), 7.54 (1 H, dd), 7.43-7.33 (2 H,m), 7.04 (1 H, s), 6.28-6.20 (1 H, m), 4.24-4.15 (2 H, m), 3.80-3.67 (2H, m), 3.63 (3 H, s), 2.73 (2 H, q), 2.69-2.55 (2 H, m), 1.32 (3 H, t)211 ¹H NMR (400 MHz, MeOD-d₄) δ ppm 7.91 (2 H, dd), 7.48-7.31 (3 H, m),7.12 (2 H, t), 6.95 (1 H, s), 3.77-3.68 (1 H, m), 3.61 (3 H, s),3.51-3.40 (2 H, m), 2.87-2.74 (2 H, m), 2.69 (2 H, q), 2.02-1.90 (2 H,m), 1.73-1.59 (2 H, m), 1.31 (3 H, t) 212 ¹H NMR (300 MHz, MeOD-d₄) δppm 7.92-7.84 (2 H, m), 7.50-7.31 (5 H, m), 7.04 (1 H, s), 3.71 (2 H,t), 3.62 (3 H, s), 3.18-3.05 (4 H, m), 2.76-2.66 (6 H, m), 2.60 (2 H,t), 1.32 (3 H, t) 213 ¹H NMR (400 MHz, MeOD-d₄) δ ppm 7.87 (2 H, d),7.57 (1 H, bd), 7.50 (1 H, d), 7.43-7.36 (3 H, m), 7.04 (1 H, s),3.71-3.64 (4 H, m), 3.62 (3 H, s), 3.24-3.17 (4 H, m), 2.70 (2 H, q),1.31 (3 H, t) 214 ¹H NMR (400 MHz, MeOD-d₄) δ ppm 7.90-7.86 (3 H, m),7.60 (1 H, dd), 7.51 (1 H, d), 7.12-7.07 (2 H, m), 6.93 (1 H, s), 6.18(1 H, bs), 4.04 (2 H, bs), 3.61 (3 H, s), 3.59 (2 H, t), 2.71 (2 H, q),2.55-2.38 (2 H, m), 1.45 (9 H, t), 1.31 (3 H, t) 215 ¹H NMR (400 MHz,MeOD-d₄) δ ppm 7.94-7.82 (3 H, m), 7.52 (1 H, d), 7.38 (1 H, dd), 7.11(2 H, t), 6.94 (1 H, s), 4.66 (1 H, d), 4.07 (1 H, d), 3.62 (3 H, s),3.16 (1 H, t), 2.89 (1 H, t), 2.79-2.57 (3 H, m), 2.42 (2 H, q), 1.88 (2H, t), 1.77-1.51 (2 H, m), 1.31 (3 H, t), 1.11 (3 H, t) 216 ¹H NMR (400MHz, CDCl₃) δ ppm7.90-7.83 (2 H, m), 7.61 (1 H, s), 7.55 (1 H, d), (Gen-7.18 (1 H, dd), 7.10 (2 H, t), 6.67 (1 H, s), 3.61 (3 H, s), 3.21-3.14(2 H, m), 3.82-3.67 (4 H, 10- m), 2.65-2.55 (1 H, m), 2.88-2.78 (2 H,m), 2.70-2.51 (2 H, m), 1.34 (3 H, t) c) 217 ¹H NMR (400 MHz, MeOD-d₄) δppm 7.90-7.80 (2 H, m), 7.80 (1 H, bs), 7.51-7.49 (1 H, m), 7.37 (1 H,dd), 7.33 (5 H, m), 7.12-7.08 (2 H, m), 6.92 (1 H, s), 3.60 (3H, s),3.54 (2 H, s), 2.99 (2 H, d), 2.70 (2H, q), 2.65-2.56 (1 H, m),2.22-2.06 (2 H, m), 1.87-1.67 (4 H, m), 1.31 (3 H, t) 218 ¹H NMR (400MHz, MeOD-d₄) δ ppm 7.89-7.86 (2 H, m), 7.81 (1 H, s), 7.51 (1 H, d),7.38 (1 H, dd), 7.13-7.08 (2 H, m), 6.93 (1 H, s), 3.61 (3 H, s),3.02-2.97 (2 H, m), 2.81-2.57 (4 H, m), 2.32 (2 H, t), 1.90-1.84 (2 H,m), 1.79-1.62 (2 H, m), 1.31 (3 H, t), 1.11-1.05 (6 H, m) 219 ¹H NMR(400 MHz, MeOD-d₄) δ ppm 7.95-7.82 (3 H, m), 7.51 (1 H, dd), 7.37 (1 H,dd), 7.11 (2 H, t), 6.93 (1 H, s), 4.18 (2 H, bd), 3.61 (3 H, s),2.87-2.76 (1 H, m), 2.75-2.62 (4 H, m), 1.81 (2 H, d), 1.59 (2 H, qd),1.44 (9 H, s), 1.31 (3 H, t) 220 ¹H NMR (400 MHz, MeOD-d₄) δ ppm7.86-7.91 (3 H, m), 7.60 (1 H, dd), 7.52 (1 H, dd), 7.07-7.14 (2 H, m),6.94 (1 H, s), 6.31-6.27 (1 H, m), 4.31-4.26 (2 H, m), 3.87 (2 H, t),3.62 (3 H, s), 2.71 (2 H, q), 2.38-2.52 (2 H, m), 1.31 (3 H, t) 221 ¹HNMR (400 MHz, MeOD-d₄) δ ppm 7.90-7.80 (3 H, m), 7.60 (1 H, dd), 7.52 (1H, dd), 7.39-7.31 (2 H, m), 7.01 (1 H, s), 6.30-6.24 (1 H, m), 4.29-4.23(2 H, m), 3.86 (2 H, t), 3.61 (3 H, s), 2.70 (2 H, q), 2.53-2.35 (2 H,m), 1.31 (3 H, t)

Biological Examples Example 3 In Vitro Assays 3.1. Principle

The principle of the assay consists in quantifying the released cholinewith an enzymatic method using choline oxidase and peroxidase. Cholineoxydation by choline oxydase releases betaine and peroxide. The latteris quantified in presence of HRP that converts the peroxide detectionagent TOOS and 4-aminoantipyrine into quinoneimine dye. The appearanceof quinoneimine dye is measured spectrophotometrically at 555 nm and isproportional to the amount of choline released by ENPP2. Inhibition ofENPP2 will result in a decrease of the signal.

3.2. Human ENPP2 (hENPP2) Assay

3.2.1. LPC as Substrate

Compound IC₅₀ values are determined in a hENPP2 (UniProtKB/SwissProtSequence ref Q13822) biochemical assay using LPC as substrate.

5 μL of a dilution series of compound, starting from 20 μM highestconcentration, 1/5 dilution, is added to the wells. hENPP2 is used at afinal concentration of 1 μg/mL or 3 μg/mL (it will be appreciated by theskilled person that the potency read out is independent of the enzymeconcentration). The enzyme is diluted in 50 mM Tris-HCl pH 8.5, 500 mMNaCl, 5 mM KCl, 10 mM CaCl₂, 0.1% fatty acid free BSA in a total volumeof 10 μL. the reaction is started by the addition of 10 μL of 150 μM LPC(palmitoyl 16:0) diluted in the same buffer as described above and themixture is incubated at 37° C. for 30 min. The reaction is terminatedand choline quantified by the addition of a 25 μL of a mixturecontaining 0.6 U/mL of choline oxidase, 0.6 U/mL of peroxydase, 1.8 mMTOOS, 1.2 mM amino-antipyrine, 20 mM EGTA (stop-developer solution)diluted in the buffer described above. Luminescence is read on theEnvision after an incubation of 30 min at room temperature (Excitation555 nm, excitation light=70%).

TABLE V LPC hENPP2 assay IC₅₀ of the compounds of the invention. Cpd #LPC-IC₅₀ 2 *** 4 *** 5 *** 12 **** 22 **** 23 * 24 *** 25 *** 26 *** 27*** 28 *** 29 *** 30 **** 31 **** 32 *** 33 ** 34 *** 35 *** 36 *** 37 *38 * 39 * 40 * 41 * 42 * 43 * 44 * 45 * 46 * 47 * 48 * 49 * 50 ** 51 *52 * 53 * 54 ** 55 * 56 ** 57 * 58 * 59 * 60 * 61 * 62 * 63 * 64 * 65 *66 * 67 * 68 * 69 * 70 * 71 * 72 *** 73 * 74 * 75 ** 76 * 77 * 78 * 79 *80 ** 81 * 82 * 83 * 84 * 85 * 86 * 87 *** 88 *** 89 *** 90 ** 91 **92 * 93 *** 94 ** 95 * 96 *** 97 *** 98 ** 99 * 100 * 101 * 102 * 103*** 104 * 105 *** 106 * 107 ** 108 * 109 *** 110 *** 111 *** 112 *** 113*** 114 *** 115 **** 116 *** 117 *** 118 *** 119 ** 121 ** 122 ** 123 *124 * 125 * 126 *** 127 ** 128 *** 129 *** 130 *** 131 *** 132 * 133 ***134 ** 135 * 136 *** 137 * 138 **** 139 **** 140 **** 141 **** 142 ****143 **** 144 **** 145 **** 146 ** 147 *** 148 * 149 *** 150 ** 151 **152 ** 153 ** 154 *** 155 ** 156 ** 157 * 158 *** 159 **** 160 *** 161 *162 *** 163 ** 164 **** 165 *** 166 **** 167 **** 168 **** 169 **** 170**** 171 **** 172 *** 173 **** 174 **** 175 ** 176 * 177 ** 178 ***179 * 180 * 182 * 183 * 184 * 185 * 186 * 187 * 188 * 189 * 190 * 191 *192 ** 193 * 194 * 195 * 196 * 197 * 198 * 199 * 200 * 201 * 202 * 203 *204 * 205 ** 206 * 207 * 208 * 209 * 210 * 211 * 212 * 213 * 214 * 215*** 216 * 217 * 218 * 219 * 220 * 221 * 222 ** 223 *** 224 * 225 * 226 *227 * 228 * 229 * 233 not active 239 * * >1000 nM ** >500-1000 nM*** >100-500 nM **** 0.01-100 nM

3.2.2. FS-3 as Substrate

Compound IC₅₀ values are determined in a fluorescent hENPP2(UniProtKB/SwissProt Sequence ref Q13822) biochemical assay using thefluorogenic autotaxin substrate FS-3 as substrate. FS-3 is a doublylabeled analog of LPC wherein the fluorophore is quenched throughintramolecular energy transfer. Without hENPP2, the emission of theprobe is quenched. If the substrate is hydrolyzed by hENPP2, theemission of the probe is not quenched anymore resulting in afluorescence increase. Inhibition of hENPP2 by compounds will result ina decrease of the signal.

10 μL of a dilution series of compound, starting from 20 μM highestconcentration, 1/5 dilution, is added to the wells. hENPP2 is used at afinal concentration of 0.4 μg/mL or 0.64 μg/mL (it will be appreciatedby the skilled person that the potency read out is independent of theenzyme concentration). The enzyme is diluted in 50 mM Tris-HCl pH 8.0,250 mM NaCl, 5 mM KCl, 1 mM MgCl₂, 1 mM CaCl₂, 0.1% fatty acid free BSAin a total volume of 20 μL. Enzyme mixture is added to compounds and theresulting mixture is incubated for 30 min at room temperature undershaking. The reaction is started by the addition of 20 μL of 0.75 μMFS-3 diluted in the same buffer as described above and the mixture isincubated at 30° C. for 30 min. Fluorescence is read on the Envision(Excitation 485 nm, emission 520 nM).

TABLE VI FS3 hENPP2 assay IC₅₀ of the compounds of the invention. Cpd #FS3-IC₅₀  2 ****  4 ****  5 ****  12 ****  22 ****  23 ****  24 ****  25****  27 ****  35 ****  36 ****  38 ****  39 ****  40 ****  41 ****  42****  43 ****  46 ****  47 ****  49 ****  50 ****  51 ****  52 ****  53****  54 ****  55 ****  56 ****  57 ****  58 ****  59 ****  60 ****  61****  62 ****  63 ****  64 ****  65 ****  66 ****  67 ****  68 ****  69****  74 ****  75 ****  76 ****  77 ****  78 ****  79 ****  80 ****  81****  82 ****  86 ****  87 ****  88 ****  89 ****  90 ****  91 ****  92****  93 ****  94 ****  95 ****  96 ****  98 ****  99 **** 100 **** 101**** 103 **** 105 **** 106 **** 108 **** 109 **** 110 **** 111 **** 112**** 113 **** 114 **** 115 **** 116 **** 118 **** 124 **** 125 **** 126**** 128 **** 133 **** 134 **** 135 **** 136 **** 137 **** 138 **** 141**** 143 **** 145 **** 147 **** 155 **** 156 **** 157 **** 158 **** 159**** 160 **** 162 **** 166 **** 167 **** 168 **** 170 **** 171 **** 172**** 173 **** 174 **** 179 **** 180 **** 182 **** 183 **** 184 **** 185**** 186 **** 187 **** 188 **** 189 **** 191 **** 192 **** 194 **** 199*** 200 **** 201 **** 203 **** 204 **** 206 **** 207 **** 208 **** 209**** 210 **** 211 **** 212 **** 213 **** 214 **** 215 **** 216 **** 217**** 218 **** 219 **** 220 **** 221 **** 224 **** 225 **** 226 **** 227**** 229 *** 230 **** 231 **** 232 **** 233 **** 234 **** 235 **** 236*** 237 **** 238 *** 239 **** Gen-10-e **** * >1000 nM ** >500-1000 nM*** >100-500 nM **** 0.01-100 nM3.3. Mouse ENPP2 (mENPP2)

3.3.1. LPC as Substrate

Compound IC₅₀ values are determined in a mENPP2 (UniProtKB/SwissProtSequence ref Q9R1E6) biochemical assay using LPC as substrate.

Five μL of a dilution series of compound, starting from 20 μM highestconcentration, 1/5 dilution, is added to the wells. mENPP2 is used at afinal concentration of 1 μg/mL. The enzyme is diluted in 50 mM Tris-HClpH 8.5, 500 mM NaCl, 5 mM KCl, 10 mM CaCl₂, 0.1% fatty acid free BSA ina total volume of 10 μL. the reaction is started by the addition of 10μL of 150 μM LPC (palmitoyl 16:0) diluted in the same buffer asdescribed above and the mixture is incubated at 37° C. for 30 min. Thereaction is terminated and choline quantified by the addition of a 25 μLof a mixture containing 0.6 U/mL of choline oxidase, 0.6 U/mL ofperoxydase, 1.8 mM TOOS, 1.2 mM amino-antipyrine, 20 mM EGTA(stop-developer solution) diluted in the buffer described above.Luminescence is read on the Envision after an incubation of 30 min atroom temperature (Excitation 555 nm, excitation light=70%).

3.3.2. FS-3 as Substrate

Compound IC50 values are determined in a fluorescent mENPP2(UniProtKB/SwissProt Sequence ref Q9R1E6) biochemical assay using thefluorogenic autotaxin substrate FS-3 as substrate. FS-3 is a doublylabeled analog of LPC wherein the fluorophore is quenched throughintramolecular energy transfer. Without mENPP2, the emission of theprobe is quenched. If the substrate is hydrolyzed by mENPP2, theemission of the probe is not quenched anymore resulting in afluorescence increase. Inhibition of mENPP2 by compounds will result ina decrease of the signal.

10 μL of a dilution series of compound, starting from 20 μM highestconcentration, 1/5 dilution, is added to the wells. mENPP2 is used at afinal concentration of 0.4 μg/mL. The enzyme is diluted in 50 mMTris-HCl pH 8.0, 250 mM NaCl, 5 mM KCl, 1 mM MgCl₂, 1 mM CaCl₂, 0.1%fatty acid free BSA in a total volume of 20 μL. Enzyme mixture is addedto compounds and the resulting mixture is incubated for 30 min at roomtemperature under shaking. The reaction is started by the addition of 20μL of 0.75 μM FS-3 diluted in the same buffer as described above and themixture is incubated at 30° C. for 30 min. Fluorescence is read on theEnvision (Excitation 485 nm, emission 520 nM).

Example 4 Whole Blood Assay 4.1. Human LPA Assay

Blood is collected from healthy volunteers who gave informed consentinto sodium heparin tubes by venipuncture, then gently inverted severaltimes to prevent clotting. Tubes are centrifuged at 3000 rpm for 15 minat 4° C. then plasma is stored at −80° C. Compounds are diluted in DMSOin concentration dependent manner then 0.5 μL are dispensed into 96-wellplate placed in ice. Plasma is defrosted on ice then 49.5 μL of plasmaare added into the well containing 0.5 μL of compound (1% DMSO final).Plates are covered with a lid in polypropylene and incubated at +37° C.,5% CO₂, for 2 h under gentle shaking (except controls which are storedat −20° C.).

At the end of the incubation, controls are defrosted in ice andtransferred in the incubated plates for LC-MS/MS analysis with a nonGLP-validated method. For the analysis, plasma proteins from a 10 μLincubated plates are precipitated with an excess of methanol containingthe internal standard, LPA 17:0. After centrifugation, the correspondingsupernatant is injected on a C18 column. Analytes are eluted out of thecolumn under isocratic conditions. An API5500 QTRAP mass spectrometer(ABSciex™) is used for the detection of LPA 18:2. No calibration curveis prepared for LPA 18:2, however relative quantities are evaluatedbased on the peak area.

TABLE VII Human whole blood assay IC₅₀ of the compounds of theinvention. Cpd # IC₅₀ 2 *** 12 *** 13 *** 80 * 110 * * >1000 nM** >500-1000 nM *** >100-500 nM **** 0.01-100 nM

4.2. Rat or Mouse LPA Assay

Whole blood is collected from rats or mouse by exsanguinations on sodiumheparin tube, then after centrifugation at 3000 rpm for 15 min at 4° C.,plasma is stored at −80° C. Compounds are diluted in DMSO inconcentration dependent manner then 0.5 μL are dispensed into 96-wellplate placed in ice. Plasma is defrosted on ice then 49.5 μL of plasmaare added into the well containing 0.5 μL of compound (1% DMSO final).Plates are covered with a lid in polypropylene and incubated at +37° C.,5% CO₂, for 2 h under gentle shaking (except controls which are storedat −20° C.).

At the end of the incubation, controls are defrosted in ice andtransferred in the incubated plates for LC-MS/MS analysis with a nonGLP-validated method. For the analysis, plasma proteins from a 10 μLincubated plates are precipitated with an excess of methanol containingthe internal standard, LPA 17:0. After centrifugation, the correspondingsupernatant is injected on a C18 column. Analytes are eluted out of thecolumn under isocratic conditions. An API5500 QTRAP mass spectrometer(ABSciex™) is used for the detection of LPA 18:2. No calibration curveis prepared for LPA 18:2, however relative quantities are evaluatedbased on the peak area.

TABLE VIII Rat whole blood assay IC₅₀ of the compounds of the invention.Cpd # IC₅₀ 2 ** 3 *** 4 *** 5 ** 6 *** 10 *** 12 **** 13 **** 14 **** 15** 16 ** 18 **** 19 * 26 * 40 ** 46 * 48 * 53 * 54 * 56 * 58 * 66 * 72 *75 * 80 ** 87 *** 88 *** 91 * 94 ** 95 *** 96 **** 98 *** 110 * 111 **112 *** 113 *** 114 ** 115 **** 136 **** 138 **** 140 **** 141 **** 142**** 143 **** 144 **** 145 **** 147 *** 149 * 154 ** 155 *** 156 * 159*** 160 **** 162 *** 166 ** 167 *** 170 *** 171 *** 173 *** 174 **** 175*** 180 * 182 * 187 *** 188 * 192 * 203 * 206 * 212 * 213 *226 * * >1000 nM ** >500-1000 nM *** >100-500 nM **** 0.01-100 nM

Example 5 In Vivo Models 5.1. Tobacco Smoke (TS) Model 5.1.1. LungsInflammatory Cells Recruitment Evaluation 5.1.1.1. Overview

The aim of this experiment is to evaluate the efficacy and potency of atest compound administered p.o., once or twice daily on days 6 to 11, vsreference compounds, on pulmonary inflammation induced by 11 days ofTS-exposure in female C57BL/6J mice, by assessing the effect of a testcompound on the tobacco smoke induced recruitment of inflammatory cellsto the lungs.

5.1.1.2. Protocol

The test compounds are formulated in PEG200/0.5% methylcellulose (25/75,v/v) and are given at a dose volume of 10 mL/kg. Roflumilast andDexamethasone are included as positive and negative control,respectively. Each treatment group consists of 10 mice.

A first group of mice is subjected to daily TS-exposure for 5consecutive days and sacrificed on the day 6, 24 h after the finalTS-exposure.

A second group is exposed to air for 5 consecutive days (sham exposure)and sacrificed on the day 6, 24 h after the final air-exposure.

Compound and reference-treated groups are subjected to daily TS-exposurefor 11 consecutive days and sacrificed on the day 12, 24 h after thefinal TS-exposure. Mice are dosed p.o. on days 6 to 11, twice daily, 1 hprior to and 6 h after each TS-exposure, with either vehicle, or thetest compound at 3, 5, 10 or 30 mg/kg. Another group is dosed p.o. ondays 6 to 11, once daily, 1 h prior to each TS-exposure, with eithervehicle, or the test compound at 10 mg/kg.

An additional group is dosed p.o., once daily, on days 6 to 11, withroflumilast at 5 mg/kg, 1 h prior to each TS-exposure. Dexamethasone isdosed p.o., twice daily, on days 6 to 11, at 0.3 mg/kg, 1 h prior to and6 h after each TS-exposure.

For each mouse, a BAL is performed using 0.4 mL of PBS. The lavage fluidis centrifuged, the supernatant removed and the resulting cell pelletre-suspended for total cell counts and cytospin slide preparation. Theremaining cells are re-pelleted and frozen. The supernatants are storedat −40° C. for possible future analysis.

The lungs are dissected out and the left lobes are removed, snap-frozenand stored at −80° C. The right lobes are inflated with 10% phosphatebuffered formalin (PBF) to a pressure of 18 cm PBF for 20 min and thenimmersed in PBF. After 24 h, the right lobe samples are transferred to70% ethanol and stored at room temperature. Cell data are presented asindividual data points for each animal and the mean value calculated foreach group.

Data are subjected to an unpaired Students ‘t’ test. Data from othergroups are initially subjected to a one-way analysis of variance test(ANOVA), followed by a Bonferroni correction for multiple comparisons inorder to test for differences between treatment groups. A ‘p’ value of<0.05 is considered to be statistically significant.

Percentage inhibitions for the cell data are calculated using theformula below:

${\% {\mspace{11mu} \;}{i{nhibition}}} = \left( {1 - {\left( \frac{{{{treatmen}t}\mspace{14mu} {group}\mspace{14mu} {result}} - {{sham}\mspace{14mu} {group}\mspace{14mu} {result}}}{{{TS}\mspace{14mu} {vehicule}\mspace{14mu} {g{roup}}\mspace{14mu} {result}} - {{sham}\mspace{14mu} {group}\mspace{14mu} {result}}} \right)*100}} \right.$

5.1.1.3. Results

For example, when tested in this protocol, Compound 2 and 12significantly inhibited the number of cells recovered in the BALF, inparticular macrophage cells, epithelial cells, and neutrophils at 10mg/kg twice daily p.o. (Compound 2 & 12) and 3 mg/kg twice daily p.o.(Compound 2).

5.1.2. Compound Efficacy and Potency Evaluation 5.1.2.1. Overview

A second tobacco smoke (TS) experiment is carried out, aimed atevaluating the efficacy and potency of a test compound administeredp.o., twice daily on days 6 to 11, vs a reference compound, on pulmonaryinflammation induced by 11 days of TS-exposure, reading out the effectson gene expression in the lungs. This second experiment consisted of 4groups of mice.

5.1.2.2. Protocols

Three groups of mice are subjected to daily TS-exposure for 11consecutive days and sacrificed on the day 12, 24 h after the finalTS-exposure. Two groups are dosed, p.o., on days 6 to 11, twice daily(b.i.d.), 1 h prior to and 6 h after each TS-exposure, with eithervehicle or the test compound at 10 mg/kg. The third group is dosed p.o.,on days 6 to 11, once daily (q.d.) with Roflumilast at 5 mg/kg, 1 hprior to each TS-exposure. This group receives vehicle 6 h after eachTS-exposure. One further group is exposed to air for 11 consecutive daysand receive vehicle 1 h prior to and 6 h after exposure on days 6 to 11.This group is also sacrificed on the day 12, 24 h after the finalexposure.

All groups receive a final dose, of the relevant treatment, 2 h prior tosacrifice on day 12. One final group is exposed to air for 11consecutive days and received vehicle 1 h prior to and 6 h afterexposure on days 6 to 11. This group is also sacrificed on the day 12,24 h after the final exposure. Mice receive a dose volume of 10 mL/kg.Each group consists in 10 subjects.

Mice are euthanized, by intra-peritoneal barbiturate anaestheticoverdose, on day 12, 24 h after the final air or TS-exposure. All micereceive a final dose of the relevant treatment, 2 h prior to sacrifice.The lungs are dissected out and placed in RNAse-free 15 mL tubescontaining ˜5 ml of RNAlater solution, ensuring the tissue is completelysubmerged. The lungs are stored overnight at 4° C. Following overnightincubation, the lungs are removed from RNAlater, the left and rightlobes are separated, placed in individual tubes and stored at −80° C.

RNA extractions are performed for 5 mice per group using Qiagen RNeasyMini Kit according to the manufacturer's specifications (Animal tissueprotocol). Total RNA are then eluted in RNase-free water (30 μl for fourreference samples and 50 μl for the twenty-four test samples). Qualityof the samples is assessed by measurement of their concentration in RNAusing a NanoDrop ND-1000 spectrophotometer and by the measurement of RNAintegrity using an 2100 Bioanalyzer (Agilent Technologies).

RNA preparations are of good quality (RIN value lies between 7.6 and9.2) and subjected to quantitative real-time PCR (QrtPCR), whichinvolved a first cDNA synthesis step. To this end, 300 ng of total RNAare reverse transcribed using the High capacity cDNA synthesis Kit(Applied Biosystems™) with random hexamers. Quantitative PCR reactionsare performed using Quanti-Fast SYBR® Green PCR Master Mix (Qiagen™) andgene-specific primer pairs for 13-actin (Eurogentech™) and QuantiTectprimer assays for all other tested genes (Qiagen™). For the genes ofinterest, the following Quantitect primer pairs are used: CCL2(QT00167832); CDK1 (QT00167734); SAA3 QT00249823), TIMP1 (QT00996282);Slc26a4 (QT00131908); LCN2 (QT00113407); CXCL5 (QT01658146), MMP12(QT00098945); PLA1a (QT00161448); TNFsF11 (QT00147385). Reactions arecarried out with a denaturation step at 95° C. for 5 min, followed by 40cycles (95° C. for 10 sec, 60° C. for 1 min) in a ViiATM7 Real-Time PCRSystem (Applied Biosystems™).

Real-time PCR data for each target gene are expressed as 2^(−ΔΔct)relative quantification versus endogenous β-actin. For statisticalanalysis, a 2-way analysis of variance (ANOVA) followed by a Dunnett'spost-hoc test versus the TS-vehicle group is performed.

The relevance of CCL2, CDK1, SAA3, TIMP1, Slc26a4, LCN2, CXCL5, MMP12,PLA1a, and TNFsF11 towards COPD is well-established through literaturedata based on patient specimen. A reference towards the relevant paperfor each gene is provided in Table IX below.

5.1.2.3. Results

The increase in relative expression levels caused by the tobacco smoketreatment is indicated in the column ‘Fold change TS+vehicle’. Thepronounced increase in the expression of this relevant gene set upontobacco smoke treatment further validates the relevance of the modelapplied. Treatment of mice with 10 mg/kg bid of Compound 2 strongly andsignificantly reduces the increase caused by the tobacco smoketreatment. The statistical significance of the compound treatment isindicated in Table VI (*p<0.05, **p<0.01, ***p<0.001 vs TS/vehicle).Roflumilast, an approved treatment for COPD, is taken along as positivecontrol in the experiment.

The inhibition of ENPP2 in a therapeutic setting strongly suppresses theincrease in expression of disease-relevant genes in lungs of tobaccosmoke-treated mice, providing a strong support for key a role of ENPP2in the pathogenesis of COPD.

TABLE IX TS induced relative expression levels in selected genes GeneFold change Fold change TS + Name TS + vehicle Compound 2 Literaturereference CCL2 7.23 3.96 * (Llinàs, et al., 2011) SAA3 105.98 6.87 ***(Bozinovski, et al., 2008) TIMP1 4.76 1.34 *** (Tilley, et al., 2011)SLC26A4 4.27 2.17 *** (Nakao, et al., 2008) LCN2 7.76 2.54 *** (Eagan,et al., 2010) MMP12 14.40 4.99 ** (Demedts, et al., 2006)

5.2. CIA Model 5.2.1. Materials

Completed Freund's adjuvant (CFA) and incomplete Freund's adjuvant (IFA)are purchased from Difco. Bovine collagen type II (CII),lipopolysaccharide (LPS), and Enbrel is obtained from Chondrex (Isled'Abeau, France); Sigma (P4252, L'Isle d'Abeau, France), Whyett (25 mginjectable syringe, France) Acros Organics (Palo Alto, Calif.),respectively. All other reagents used are of reagent grade and allsolvents are of analytical grade.

5.2.2. Animals

Dark Agouti rats (male, 7-8 weeks old) are obtained from HarlanLaboratories (Maison-Alfort, France). Rats are kept on a 12 h light/darkcycle (07:00-19:00). Temperature is maintained at 22° C., and food andwater are provided ad libitum.

5.2.3. Collagen Induced Arthritis (CIA)

One day before the experiment, CII solution (2 mg/mL) is prepared with0.05 M acetic acid and stored at 4° C. Just before the immunization,equal volumes of adjuvant (IFA) and CII are mixed by a homogenizer in apre-cooled glass bottle in an ice water bath. Extra adjuvant andprolonged homogenization may be required if an emulsion is not formed.0.2 mL of the emulsion is injected intradermally at the base of the tailof each rat on day 1, a second booster intradermal injection (CIIsolution at 2 mg/mL in CFA 0.1 mL saline) is performed on day 9. Thisimmunization method is modified from published methods (Sims, et al.,2004) (Jou, et al., 2005).

5.2.4. Study Design

The therapeutic effects of the compounds are tested in the rat CIAmodel. Rats are randomly divided into equal groups and each groupcontains 10 rats. All rats are immunized on day 1 and boosted on day 9.Therapeutic dosing lasted from day 16 to day 30. The negative controlgroup is treated with vehicle and the positive control group with Enbrel(10 mg/kg, 3×/week, s.c.). A compound of interest is typically tested at4 doses, e.g. 0.3, 1, 3, and 10 mg/kg, p.o.

5.2.5. Clinical Assessment of Arthritis

Arthritis is scored according to literature-described method((Khachigian, 2006) (Lin, et al., 2007), (Nishida, et al., 2004)). Theswelling of each of the four paws is ranked with the arthritic score asfollows: 0-no symptoms; 1-mild, but definite redness and swelling of onetype of joint such as the ankle or wrist, or apparent redness andswelling limited to individual digits, regardless of the number ofaffected digits; 2-moderate redness and swelling of two or more types ofjoints; 3-severe redness and swelling of the entire paw includingdigits; 4-maximally inflamed limb with involvement of multiple joints(maximum cumulative clinical arthritis score 16 per animal) (Nishida, etal., 2004).

To permit the meta-analysis of multiple studies the clinical scorevalues are normalised as follows:

AUC of Clinical Score (AUC Score):

The area under the curve (AUC) from day 1 to day 14 is calculated foreach individual rat. The AUC of each animal is divided by the averageAUC obtained for the vehicle in the study from which the data on thatanimal is obtained and multiplied by 100 (i.e. the AUC is expressed as apercentage of the average vehicle AUC per study).

Clinical Score Increase from Day 1 to Day 14 (End Point Score):

The clinical score difference for each animal is divided by the averageclinical score difference obtained for the vehicle in the study fromwhich the data on that animal is obtained and multiplied by 100 (i.e.the difference is expressed as a percentage of the average clinicalscore difference for the vehicle per study).

5.2.6. Change in Body Weight (%) after Onset of Arthritis

Clinically, body weight loss is associated with arthritis (Shelton,Zeller, Ho, Pons, & Rosenthal, 2005); (Rall & Roubenoff, 2004);(Walsmith, Abad, Kehayias, & Roubenoff, 2004)). Hence, changes in bodyweight after onset of arthritis can be used as a non-specific endpointto evaluate the effect of therapeutics in the rat model. The change inbody weight (%) after onset of arthritis is calculated as follows:

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5.2.7. Radiology

X-ray photos are taken of the hind paws of each individual animal. Arandom blind identity number is assigned to each of the photos, and theseverity of bone erosion is ranked by two independent scorers with theradiological Larsen's score system as follows: 0—normal with intact bonyoutlines and normal joint space; 1—slight abnormality with any one ortwo of the exterior metatarsal bones showing slight bone erosion;2—definite early abnormality with any three to five of the exteriormetatarsal bones showing bone erosion; 3—medium destructive abnormalitywith all the exterior metatarsal bones as well as any one or two of theinterior metatarsal bones showing definite bone erosions; 4—severedestructive abnormality with all the metatarsal bones showing definitebone erosion and at least one of the inner metatarsal joints completelyeroded leaving some bony joint outlines partly preserved; 5—mutilatingabnormality without bony outlines. This scoring system is a modificationfrom literature protocols (Salvemini, et al., 2001) (Bush, Farmer,Walker, & Kirkham, 2002) (Sims, et al., 2004) (Jou, et al., 2005).

5.2.8. Histology

After radiological analysis, the hind paws of mice are fixed in 10%phosphate-buffered formalin (pH 7.4), decalcified with rapid bonedecalcifiant for fine histology (Laboratories Eurobio) and embedded inparaffin. To ensure extensive evaluation of the arthritic joints, atleast four serial sections (5 μm thick) are cut and each series ofsections are 100 μm in between. The sections are stained withhematoxylin and eosin (H&E). Histologic examinations for synovialinflammation and bone and cartilage damage are performed double blind.In each paw, four parameters are assessed using a four-point scale. Theparameters are cell infiltration, pannus severity, cartilage erosion andbone erosion. Scoring is performed according as follows: 1—normal,2—mild, 3—moderate, 4—marked. These four scores are summed together andrepresented as an additional score, namely the ‘RA total score’.

5.2.9. Micro-Computed Tomography (CT) Analysis of Calcaneus (Heel Bone)

Bone degradation observed in RA occurs especially at the cortical boneand can be revealed by μCT analysis ((Sims, et al., 2004); (Oste,Salmon, & Dixon, 2007). After scanning and 3D volume reconstruction ofthe calcaneus bone, bone degradation is measured as the number ofdiscrete objects present per slide, isolated in silico perpendicular tothe longitudinal axis of the bone. The more the bone is degraded, themore discrete objects are measured. 1000 slices, evenly distributedalong the calcaneus (spaced by about 10.8 μm), are analyzed.

5.2.10. Steady State PK

At day 7 or later, blood samples are collected at the retro-orbitalsinus with lithium heparin as anti-coagulant at the following timepoints: predose, 1, 3 and 6 h. Whole blood samples are centrifuged andthe resulting plasma samples are stored at −20° C. pending analysis.Plasma concentrations of each test compound are determined by anLC-MS/MS method in which the mass spectrometer is operated in positiveelectrospray mode. Pharmacokinetic parameters are calculated usingWinnonlin® (Pharsight®, United States) and it is assumed that thepredose plasma levels are equal to the 24 h plasma levels.

5.3. Idiopathic Pulmonary Fibrosis Assay 5.3.1. Overview

The mouse bleomycin-induced fibrosis model mimics the maincharacteristics of human lung fibrosis and is used to test potential newtherapies for lung fibrosis (Walters & Kleeberger, 2008).

5.3.2. Protocol

In vivo efficacy of a compound of the invention is assessed in a 10-daysmouse preventive bleomycin-induced pulmonary fibrosis model by oralroute. Mice (20-25 g female C57BL/6; n=10-15 per group) are treated withbleomycin sulfate (1.5 U/kg) via intratracheal instillation at day 0under isoflurane anesthesia, and then treated with the compoundsaccordingly to the study protocol from day 1 to day 10. Mice are kept ona 12 hr light/dark cycle (07:00-19:00). The temperature is maintained at22° C., and food and water are provided ad libitum. At sacrifice,broncho alveolar lavage fluid (BALF; 2×0.75 mL PBS) is collected fromlungs. This material is used to determine

-   -   the amount of infiltrated inflammatory cells:    -   All the BALF cells (for example macrophage, eosinophil,        neutrophil and epithelial cells) are pelleted, resuspended in        PBS and counted    -   the total amount of proteins using a Bradford dosing: this        readout reflects the vascular leakage occurring, leading to the        formation of an exudates in the lungs    -   the amount of collagen using a Sircol™ dosing (Available from        Biocolor Ltd., 8 Meadowbank Road, Carrickfergus, BT38 8YF,        County Antrim, UK)    -   This readout reflects the level of extra-cellular matrix        degradation and tissue remodeling occurring in the lungs.

One lung of each mouse is also collected and prepared for histologicalanalysis using 10% neutral buffered formalin.

5.4. Septic Shock Model

Injection of lipopolysaccharide (LPS) induces a rapid release of solubletumour necrosis factor (TNF-alpha) into the periphery. This model isused to analyse prospective blockers of TNF release in vivo.

Six BALB/cJ female mice (20 g) per group are treated at the intendeddosing once, po. Thirty min later, LPS (15 μg/kg; E. Coli serotype0111:B4) is injected ip. Ninety min later, mice are euthanized and bloodis collected. Circulating TNF alpha levels are determined usingcommercially available ELISA kits. Dexamethasone (5 μg/kg) is used as areference anti-inflammatory compound.

5.5. MAB Model

The MAB model allows a rapid assessment of the modulation of an RA-likeinflammatory response by therapeutics (Khachigian, 2006). DBA/J mice areinjected i.v. with a cocktail of mAbs directed against collagen II. Oneday later, compound treatment is initiated. Three days later, micereceive an i.p. LPS injection (50 μg/mouse), resulting in a fast onsetof inflammation. Compound treatment is continued until 10 days after themAb injection. Inflammation is read by measuring paw swelling andrecording the clinical score of each paw. The cumulative clinicalarthritis score of four limbs is presented to show the severity ofinflammation. A scoring system is applied to each limb using a scale of0-4, with 4 being the most severe inflammation.

-   -   0 Symptom free    -   1 Mild, but definite redness and swelling of one type of joint        such as the ankle or wrist, or apparent redness and swelling        limited to individual digits, regardless of the number of        affected digits    -   2 Moderate redness and swelling of two or more types of joints    -   3 Severe redness and swelling of the entire paw including digits    -   4 Maximally inflamed limb with involvement of multiple joints

5.6. Mouse IBD Model

The mouse chronic dextran sodium sulphate (DSS)-induced inflammatorybowel disease (IBD) model is a well validated disease model forinflammatory bowel disease (Sina, et al., 2009) (Wirtz, Neufert,Weigmann, & Neurath, 2007).

To induce a chronic colitis, female BALB/c mice are fed with 4% DSSdissolved in drinking water for 4 days, followed by 3 days of regulardrinking water. This cycle is repeated three times. This protocolinduces a strong colitis while avoiding high mortality rates. Animalsare divided into several groups:

-   -   a. intact (water; vehicle alone, n=10),    -   b. diseased (DSS; vehicle alone, n=10),    -   c. sulfazalazine used as reference (DSS; 20 mg/kg/day        sulfazalazine, p.o., n=10) and    -   d. the tested compound (DSS; 1, 3, 10 and 30 mg/kg/day test        compound, p.o., n=10/dose).

Clinical parameters are measured daily. The disease activity index (DAI)is a combination of the individual scores for weight loss, stoolconsistency and rectal bleeding. At necropsy, the complete colons areremoved and rinsed with sterile PBS. Segments of the distal colon aredissected for histological analysis, gene expression and protein levelmeasurement.

5.7. Mouse Asthma Model

In vitro and in vivo models to validate efficacy of small moleculestowards asthma are described by Nials et al. (Nials & Uddin, 2008) (DeAlba, et al., 2010), Park et al. (Park, et al., 2013) and Kudlacz et al.(Kudlacz, Conklyn, Andresen, Whitney-Pickett, & Changelian, 2008).

5.8. LPS Induced Lung Inflammation Model 5.8.1. Overview

The aim of the assay is to assess the effect of a test compound in amouse model of acute lung inflammation induced by intranasalinstillation of LPS. The impact on the induced cells recruitment in lungis evaluated by measurement of white cells count in broncho-alveolarlavage (BAL) fluid with VetABC device (medical solution gmbh, Hünenberg,Switzerland).

5.8.2. Protocol

The animals (BALB/c J mice, 18-20 g) are obtained from HarlanLaboratories (Maison-Alfort, France). The animals are maintained on 12hours light/dark cycle at 22° C. with ad libitum access to tap water andfood. Litters are changed twice a week. For each tested compound, agroup of 10 subjects is used. In addition to the test compound-treatedgroups, a vehicle+LPS control group (inLPS), a non-treated group(intact), and a positive control dexamethasone treated group (DEX) areused.

LPS is dissolved in saline solution in order to obtain a final 10 μg/50μL solution for intranasal instillation, and administered at 50 μL/mouseby intranasal instillation.

The test compounds are prepared in 15 mL PEG200 (9 mL)/H₂O (6 mL) to bedosed in a range of 0.3, 1, 3, 10, and 30 mg/kg, and then kept at roomtemperature in the dark, and are administered once (qd) or twice daily(bid) over 2 days.

Dexamethasone (10 mg/kg, bid, po) is used as a positive control.

On day 1, mice are anaesthetized by isoflurane inhalation. Duringbreathing, LPS solution is instilled intra-nasally and mice aremonitored until complete recovery from anaesthesia.

On day 2, mice are anaesthetized by intra-peritoneal injection (under avolume of 10 mL/kg) of anaesthetic solution (18 mL NaCl 0.9%+0.5 mLxylazine (5 mg/kg)+1.5 mL ketamine (75 mg/kg)).

The trachea is canulated with a catheter, and BAL is performed by 2×0.75mL sterile PBS.

The BAL fluid removed is shaked gently at room temperature beforecentrifugation at 1500 r.p.m. during 10 min at 4° C.

The supernatant is removed and the cell pellet is suspended in 200 μL ofPBS, kept on ice and total cell count is processed with VetABC device.Finally, mice are sacrificed under anaesthesia.

5.8.3. Data Analysis

For each readout, mean and sem are calculated. A differencestatistically significant between intact or treated groups and inLPSVehicle group is evaluated with Prism® software using a one-way ANOVA(for treatment groups) followed by a Dunnett's multiple comparisonspost-hoc test. *: p<0.05; **: p<0.01; ***: p<0.001 versus inLPS Vehiclegroup.

5.9. Pharmakokinetic Studies in Rodents and Dogs 5.9.1. Animals

Male Sprague-Dawley rats (180-200 g) and female C57BL/6Rj mice (18-22 g)are obtained from Janvier (France). Non-naïve male Beagle dogs (8-13 kg)are obtained from Marshall BioResources (Italy). Two days beforeadministration of compound, rats undergo surgery to place a catheter inthe jugular vein under isoflurane anesthesia. Before oral dosing,animals are deprived of food for at least 16 h before dosing until 4 hafter. Water is provided ad libitum. All in vivo experiments are carriedout in a dedicated pathogen free facility (22° C.).

5.9.2. Pharmacokinetic Study

Compounds are formulated in PEG200/water for injection (25/75, v/v) forthe intravenous route and in PEG200/0.5% methylcellulose (25/75, v/v)for the oral route.

5.9.2.1. Rodents

Compounds are orally dosed as a single esophageal gavage at 5 mg/kg(dosing volume of 5 mL/kg) and intravenously dosed as a bolus via thecaudal vein at 1 mg/kg (dosing volume of 5 mL/kg). In the rat studies,each group consists of three rats and blood samples are collected viathe jugular vein. In the mouse studies, each group consists of 21 mice(n=3/time point) and blood samples are collected by intra-cardiacpuncture under isoflurane anesthesia. Li-heparin is used asanti-coagulant and blood is taken at 0.05, 0.25, 0.5, 1, 3, 5, 8 and 24h (i.v. route) and 0.25, 0.5, 1, 3, 5, 8 and 24 h (p.o. route).

5.9.2.2. Dogs

Compounds are dosed to three animals i.v. via a 10 min infusion in thecephalic vein with a dose level of 1 mg/kg (dose volume of 2 mL/kg) andafter a washout of minimally 3 days, dosed orally as a single gavagewith a dose level of 5 mg/kg (dose volume of 2 mL/kg). Blood samples aretaken from the jugular vein using vacutainers and Li-heparin asanticoagulant at 0.083, 0.167, 0.5, 1, 2, 4, 6, 8, 10 and 24 h (i.v.)and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10 and 24 h (p.o.).

5.9.3. Quantification of Compound Levels in Plasma

Whole blood samples are centrifuged at 5000 rpm for 10 min and theresulting plasma samples are stored at −20° C. pending analysis. Plasmaconcentrations of each test compound are determined by an LC-MS/MSmethod

5.9.4. Determination of Pharmacokinetic Parameters

Pharmacokinetic parameters are calculated using Winnonlin® (Pharsight®,United States).

5.9.5. 5-Day Rat Toxicity Study

A 5-day oral toxicity study with test compounds is performed inSprague-Dawley male rats to assess their toxic potential andtoxicokinetics, at daily doses of 100, 300 and 600 mg/kg/day, by gavage,at the constant dosage-volume of 20 mL/kg/day.

The test compounds are formulated in PEG200/0.5% methylcellulose (25/75,v/v). Each group included 6 principal male rats as well as 3 satelliteanimals for toxicokinetics. A fourth group is given PEG200/0.5%methylcellulose (25/75, v/v) only, at the same frequency, dosage volumeand by the same route of administration, and acted as the vehiclecontrol group.

The goal of the study is to determine the lowest dose that resulted inno adverse events (no observable adverse effect level—NOAEL).

5.9.6. Hepatocyte Stability

Models to evaluate metabolic clearance in hepatocyte are described byMcGinnity et al. Drug Metabolism and Disposition 2008, 32, 11, 1247.

5.9.7. Liability for QT Prolongation

Potential for QT prolongation is assessed in the hERG patch clamp assay.

Whole-cell patch-clamp recordings are performed using an EPC10 amplifiercontrolled by Pulse v8.77 software (HEKA). Series resistance istypically less than 10 MΩ and compensated by greater than 60%,recordings are not leak subtracted. Electrodes are manufactured fromGC150TF pipette glass (Harvard).

The external bathing solution contains: 135 mM NaCl, 5 mM KCl, 1.8 mMCaCl₂, 5 mM Glucose, 10 mM HEPES, pH 7.4.

The internal patch pipette solution contains: 100 mM K-gluconate, 20 mMKCl, 1 mM CaCl₂, 1 mM MgCl₂, 5 mM Na₂ATP, 2 mM Glutathione, 11 mM EGTA,10 mM HEPES, pH 7.2.

Drugs are perfused using a Biologic MEV-9/EVH-9 rapid perfusion system.

All recordings are performed on HEK293 cells stably expressing hERGchannels. Cells are cultured on 12 mm round coverslips (German glass,Bellco) anchored in the recording chamber using two platinum rods(Goodfellow). hERG currents are evoked using an activating pulse to +40mV for 1000 ms followed by a tail current pulse to −50 mV for 2000 ms,holding potential is −80 mV. Pulses are applied every 20 s and allexperiments are performed at r.t.

Example 6 ADME 6.1. Kinetic Solubility

Starting from a 10 mM stock in DMSO, a serial dilution of the compoundis prepared in DMSO. The dilution series is transferred to a NUNCMaxisorb F-bottom 96-well plate (Cat no. 442404) and 0.1 M phosphatebuffer pH 7.4 or 0.1 M citrate buffer pH 3.0 at room temperature isadded.

The final concentration will range from 300 μM to 18.75 μM in 5 equaldilution steps. The final DMSO concentration does not exceed 3%. 200 μMpyrene is added to the corner points of each 96-well plate and serves asa reference point for calibration of Z-axis on the microscope.

The assay plates are sealed and incubated for 1 h at 37° C. whileshaking at 230 rpm. The plates are then scanned under a white lightmicroscope, yielding individual pictures of the precipitate perconcentration. The precipitate is analyzed and converted into a numberwith a software tool which can be plotted onto a graph. The firstconcentration at which the compound appears completely dissolved is theconcentration reported; however the true concentration lies somewherebetween this concentration and one dilution step higher.

Solubility values measured according to this protocol are reported in μMand μg/mL.

6.2. Plasma Protein Binding (Equilibrium Dialysis)

A 10 mM stock solution of the compound in DMSO is diluted with a factor5 in DMSO. This solution is further diluted in freshly thawed human,rat, mouse or dog plasma (BioReclamation INC) with a final concentrationof 5 μM and final DMSO concentration of 0.5% (5.5 μL in 1094.5 μL plasmain a PP-Masterblock 96-well plate (Greiner, Cat no. 780285))

A Pierce Red Device plate with inserts (ThermoScientific, Cat no. 89809)is prepared and filled with 750 μL PBS in the buffer chamber and 500 μLof the spiked plasma in the plasma chamber. The plate is incubated for 4h at 37° C. while shaking at 230 rpm. After incubation, 120 μL of bothchambers is transferred to 360 μL acetonitrile in a 96-well roundbottom, PP deep-well plate (Nunc, Cat no. 278743) and sealed with analuminum foil lid. The samples are mixed and placed on ice for 30 min.This plate is then centrifuged 30 min at 1200 RCF at 4° C. and thesupernatant is transferred to a 96-well V-bottom PP plate (Greiner,651201) for analysis on LC-MS.

The plate is sealed with sealing mats (MA96RD-04S) of Kinesis, Cambs,PE19 8YX, UK and samples are measured at room temperature on LC-MS (ZQ1525 from Waters) under optimized conditions using Quanoptimize todetermine the appropriate mass of the molecule.

The samples are analyzed by LC-MS. Peak area from the compound in thebuffer chamber and the plasma chamber are considered to be 100%compound. The percentage bound to plasma is derived from these resultsand is reported as percentage bound to plasma.

The solubility of the compound in the final test concentration in PBS isinspected by microscope to indicate whether precipitation is observed ornot.

6.3. Microsomal Stability

A 10 mM stock solution of compound in DMSO is diluted to 6 μM in a 105mM phosphate buffer, pH 7.4 in a 96 deep well plate (Greiner, Cat no.780285) and pre-warmed at 37° C.

A Glucose-6-phosphate-dehydrogenase (G6PDH, Roche, 10127671001) workingstock solution of 700 U/mL is diluted with a factor 1:700 in a 105 mMphosphate buffer, pH 7.4. A co-factor mix containing 0.528 M MgCl₂.6H₂O(Sigma, M2670), 0.528 M glucose-6-phosphate (Sigma, G-7879) and 0.208 MNADP+ (Sigma,N-0505) is diluted with a factor 1:8 in a 105 mM phosphatebuffer, pH 7.4.

A working solution is made containing 1 mg/mL liver microsomes(Provider, Xenotech) of the species of interest (e.g., human, mouse,rat, dog), 0.8 U/mL G6PDH and co-factor mix (6.6 mM MgCl₂, 6.6 mMglucose-6-phosphate, 2.6 mM NADP+). This mix is pre-incubated for 15min, but never more than 20 min, at room temperature.

After pre-incubation, compound dilution and the mix containing themicrosomes, are added together in equal amount and incubated for 30 minat 300 rpm. For the time point of 0 min, two volumes of methanol areadded to the compound dilution before the microsome mix is added. Thefinal concentration during incubation are: 3 μM test compound or controlcompound, 0.5 mg/mL microsomes, 0.4 U/mL G6PDH, 3.3 mM MgCl₂, 3.3 mMglucose-6-phosphate and 1.3 mM NaDP+.

After 30 min of incubation, the reaction is stopped with 2 volumes ofmethanol.

Of both time points, samples are mixed, centrifuged and the supernatantis harvested for analysis on LC-MS/MS. The instrument responses (i.e.peak heights) are referenced to the zero time-point samples (as 100%) inorder to determine the percentage of compound remaining. Standardcompounds Propranolol and Verapamil are included in the assay design.

The data on microsomal stability are expressed as a percentage of thetotal amount of compound remaining after 30 min.

6.4. CYP Inhibition 6.4.1. Direct CYP Inhibition

The in vitro direct inhibitory potential (IC50) of the compounds oncytochrome P450 isoenzymes in pooled human liver microsomes (HLM) isdetermined based on the draft FDA Guidance for Industry (DrugInteraction Studies—Study Design, Data Analysis, Implications forDosing, and Labeling Recommendations), 2006,http://www.fda.gov/cder/guidance/index.htm.

The following probe substrates are used: phenacetin for CYP1A2,diclofenac for CYP2C9, S(+)-mephenytoin for CYP2C19, bufuralol forCYP2D6 and testosterone for CYP3A4. The following positive controlinhibitors are used: α-naphtoflavone for CYP1A2, sulfaphenazole forCYP2C9, tranylcypromine for CYP2C19, quinidine for CYP2D6 andketoconazole for CYP3A4.

6.4.2. Time-dependent CYP3A4 inhibition

Time-dependent CYP3A4 inhibition by the compounds, assessed in pooledHLM, is determined via IC₅₀ determination according to Grimm et al. DrugMetabolism and Disposition 2009, 37, 1355-1370 and the draft FDAGuidance for Industry (Drug Interaction Studies—Study Design, DataAnalysis, Implications for Dosing, and Labeling Recommendations), 2006,http://www.fda.gov/cder/guidance/index.htm. Testosterone is used asprobe substrate and troleandomycin is used as positive control.

6.5. Caco2 Permeability

Bi-directional Caco-2 assays are performed as described below. Caco-2cells are obtained from European Collection of Cell Cultures (ECACC, cat86010202) and used after a 21 day cell culture in 24-well Transwellplates (Fisher TKT-545-020B).

2×105 cells/well are seeded in plating medium consisting ofDMEM+GlutaMAXI+1% NEAA+10% FBS (FetalClone II)+1% Pen/Strep. The mediumis changed every 2-3 days.

Test and reference compounds (propranolol and rhodamine 123 orvinblastine, all purchased from Sigma) are prepared in Hanks' BalancedSalt Solution containing 25 mM HEPES (pH 7.4) and added to either theapical (125 μL) or basolateral (600 μL) chambers of the Transwell plateassembly at a concentration of 10 μM with a final DMSO concentration of0.25%.

50 μM Lucifer Yellow (Sigma) is added to the donor buffer in all wellsto assess integrity of the cell layers by monitoring Lucifer Yellowpermeation. As Lucifer Yellow (LY) cannot freely permeate lipophilicbarriers, a high degree of LY transport indicates poor integrity of thecell layer.

After a 1 hr incubation at 37° C. while shaking at an orbital shaker at150 rpm, 70 μL aliquots are taken from both apical (A) and basal (B)chambers and added to 100 μL 50:50 acetonitrile:water solutioncontaining analytical internal standard (0.5 μM carbamazepine) in a96-well plate.

Lucifer yellow is measured with a Spectramax Gemini XS (Ex 426 nm and Em538 nm) in a clean 96-well plate containing 150 μL of liquid frombasolateral and apical side.

Concentrations of compound in the samples are measured by highperformance liquid-chromatography/mass spectroscopy (LC-MS/MS).

Apparent permeability (Papp) values are calculated from therelationship:

Papp=[compound]acceptor final×Vacceptor/([compound]donorinitial×Vdonor)/Tinc×Vdonor/surface area×60×10⁻⁶ cm/s

V=chamber volume

Tinc=incubation time.

Surface area=0.33 cm²

The Efflux ratios, as an indication of active efflux from the apicalcell surface, are calculated using the ratio of Papp B>A/Papp A>B.

The following assay acceptance criteria are used:

Propranolol: Papp (A>B) value ≧20(×10⁻⁶ cm/s)

Rhodamine 123 or Vinblastine: Papp (A>B) value <5 (×10⁻⁶ cm/s) withEfflux ratio ≧5

Lucifer yellow permeability: ≦100 nm/s

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FINAL REMARKS

It will be appreciated by those skilled in the art that the foregoingdescriptions are exemplary and explanatory in nature, and intended toillustrate the invention and its preferred embodiments. Through routineexperimentation, an artisan will recognize apparent modifications andvariations that may be made without departing from the spirit of theinvention. All such modifications coming within the scope of theappended claims are intended to be included therein. Thus, the inventionis intended to be defined not by the above description, but by thefollowing claims and their equivalents.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication are specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

It should be understood that factors such as the differential cellpenetration capacity of the various compounds can contribute todiscrepancies between the activity of the compounds in the in vitrobiochemical and cellular assays.

At least some of the chemical names of compound of the invention asgiven and set forth in this application, may have been generated on anautomated basis by use of a commercially available chemical namingsoftware program, and have not been independently verified.Representative programs performing this function include the Lexichemnaming tool sold by Open Eye Software, Inc. and the Autonom Softwaretool sold by MDL, Inc. In the instance where the indicated chemical nameand the depicted structure differ, the depicted structure will control.

1) A compound according to Formula I:

wherein R^(1a) is H, halo or C₁₋₄ alkyl; R^(1b) is: halo, C₁₋₄ alkyl(which alkyl is optionally substituted with one or more independentlyselected halo), or C₁₋₄ alkoxy (which alkoxy is optionally substitutedwith one or more independently selected halo); X is —S—, —O—, —N═CH—,—CH═N— or —CH═CH—; W is N, or CR³ when W is N, R² is: H, —CN, halo, C₁₋₄alkyl (which alkyl is optionally substituted with one or moreindependently selected OH, or CN) —C(═O)CH₃, —C(═O)CF₃, —C(═O)OCH₃,—C(═O)NH₂, or —NHC(═O)CH₃, or when W is CR³, one of R² or R³ is: H, —CN,halo, C₁₋₄ alkyl (which alkyl is optionally substituted with one or moreindependently selected OH, or CN) —C(═O)CH₃, —C(═O)CF₃, —C(═O)OCH₃,—C(═O)NH₂, or —NHC(═O)CH₃, and the other is H, or C₁₋₄ alkyl; R⁴ is C₁₋₄alkyl; R⁵ is C₁₋₄ alkyl optionally substituted with one or moreindependently selected CN, OH, halo, or —C(═O)NH₂; one of R^(6a) orR^(6b) is selected from H, —CH₃, and halo, and the other is H; Cy is:C₄₋₁₀ cycloalkyl, 4-10 membered mono or bicyclic heterocycloalkylcontaining one or more heteroatoms independently selected from O, N, andS, or 4-7 membered heterocycloalkenyl containing 1 double bond,containing one or more heteroatoms independently selected from O, N, andS; each R⁷ is independently selected from: OH, oxo, halo, and C₁₋₄ alkyl(which alkyl is optionally substituted with one or more independentlyselected OH, or C₁₋₄ alkoxy); the subscript a is 0, 1 or 2; R⁸ is-(L₁-W₁)_(m)-L₂-G₁, wherein L₁ is absent, or is —O—, —C(═O)—, —NR^(i),—NR^(h)C(═O)—, or —SO₂—; W₁ is C₁₋₄ alkylene; the subscript m is 0, or1; L₂ is absent, or is —O—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)—C(═O)—,—C(═O)—C(═O)NR^(a)—, —NR^(b)—, —C(═O)NR^(e)—, —NR^(d)C(═O)—,—NR^(j)C(═O)O—, —SO₂—, —SO₂NR^(e)— or —NR^(f)SO₂—; G₁ is H, —CN, C₁₋₄alkyl (which alkyl is optionally substituted with one or moreindependently selected —CN, OH, halo or phenyl), C₃₋₇ cycloalkyl (whichcycloalkyl is optionally substituted with —NH₂), 5-6 memberedheterocycloalkenyl containing 1 double bond containing one or moreheteroatoms independently selected from O, N, and S (whichheterocycloalkenyl is optionally substituted with one or moreindependently selected R⁹ groups), 4-10 membered mono, bi or spirocyclicheterocycloalkyl containing one or more heteroatoms independentlyselected from O, N, and S (which heterocycloalkyl is optionallysubstituted with one or more independently selected R⁹ groups), or 5-6membered heteroaryl containing one or more heteroatoms independentlyselected from O, N, and S (which heteroaryl is optionally substitutedwith one or more independently selected R¹⁰ groups), each R⁹ is oxo, orR¹⁰ each R¹⁰ is: —OH, halo, —CN, C₁₋₄ alkyl (which alkyl is optionallysubstituted with one or more independently selected OH, halo, orphenyl), C₁₋₄ alkoxy, C₃₋₇ cycloalkyl, phenyl, —SO₂CH₃, —C(═O)C₁₋₄alkoxy, —C(═O)C₁₋₄ alkyl, or —NR^(g)C(═O)C₁₋₄ alkyl; and each R^(a),R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), R^(h), R^(i), and R^(j) isindependently selected from H and C₁₋₄ alkyl; or a pharmaceuticallyacceptable salt, or a solvate, or a pharmaceutically acceptable salt ofa solvate thereof. 2) A compound or pharmaceutically acceptable saltthereof, according to claim 1, wherein the compound is according toFormula II:

3) A compound or pharmaceutically acceptable salt thereof, according toclaim 2, wherein the compound is according to Formula III:

4) A compound or pharmaceutically acceptable salt thereof, according toclaim 1, wherein R⁵ is —CH₃, or —C₂H₅. 5) A compound or pharmaceuticallyacceptable salt thereof, according to claim 2, wherein R⁵ is —CH₃, or—C₂H₅. 6) A compound or pharmaceutically acceptable salt thereof,according to claim 3, wherein R⁵ is —CH₂—CH₂—CN, —CH₂—CH₂—OH, —CH₂—CF₃,or —CH₂—CH₂—C(═O)NH₂. 7) A compound or pharmaceutically acceptable saltthereof, according to claim 1, wherein Cy is 4-10 membered mono orbicyclic heterocycloalkyl containing one or more heteroatomsindependently selected from O, N, and S. 8) A compound orpharmaceutically acceptable salt thereof, according to claim 1, whereinthe subscript a is
 0. 9) A compound according to claim 1, wherein thecompound is according to Formula Va, Vb, Vc, or Vd:

10) A compound or pharmaceutically acceptable salt thereof, according toclaim 9, wherein W₁ is —CH₂—, —CH₂—CH₂—, —C(CH₃)H—, —CH₂—CH₂—CH₂— or—CH₂—C(CH₃)H—. 11) A compound or pharmaceutically acceptable saltthereof, according to claim 10, wherein G₁ is 4-7 memberedheterocycloalkyl containing one or more heteroatoms independentlyselected from O, N, and S, which heterocycloalkyl is substituted withone or two independently selected R⁹ groups. 12) A compound orpharmaceutically acceptable salt thereof, according to claim 11, whereinR⁹ is R¹⁰ and R¹⁰ is selected from OH, F, Cl, and —CN. 13) A compound orpharmaceutically acceptable salt thereof, according to claim 12, whereinR^(6a) is H, —CH₃ or F, and R^(6b) is H. 14) A compound orpharmaceutically acceptable salt thereof, wherein the compound isselected from:2-((2-ethyl-8-methyl-6-(piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,2-((2-ethyl-6-(4-(2-(3-hydroxy-3-methylazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,(R)-2-((2-ethyl-6-(4-(2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl)piperazin-1-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,(S)-2-((2-ethyl-6-(4-(2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl)piperazin-1-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-3,3-dimethylpiperazin-1-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-8-methylimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone,(R)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-8-methylimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-(3-hydroxypyrrolidin-1-yl)ethanone,(S)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-8-methylimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-(3-hydroxypyrrolidin-1-yl)ethanone,2-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,2-(ethyl(2-ethyl-8-methyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,2-((2-ethyl-8-fluoro-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,2-(4-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethyl-8-fluoroimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-N-methylacetamide,2-(4-(2-ethyl-8-fluoro-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone,(S)-2-(4-(2-ethyl-8-fluoro-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-(3-hydroxypyrrolidin-1-yl)ethanone,(R)-2-(4-(2-ethyl-8-fluoro-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-(3-hydroxypyrrolidin-1-yl)ethanone,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-7-methylimidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone,2-[(2-Ethyl-7-fluoro-6-{4-[2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-imidazo[1,2-a]pyridin-3-yl)-methyl-amino]-4-(4-fluoro-phenyl)-thiazole-5-carbonitrile,2-[4-(2-Ethyl-7-fluoro-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-a]pyridin-6-yl)-piperazin-1-yl]-1-(3-hydroxy-azetidin-1-yl)-ethanone,2-[4-(2-Ethyl-7-fluoro-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-a]pyridin-6-yl)-piperazin-1-yl]-1-(3-hydroxy-pyrrolidin-1-yl)-ethanone,2-[4-(2-Ethyl-7-fluoro-3-{[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amino}-imidazo[1,2-a]pyridin-6-yl)-piperazin-1-yl]-1-(3-hydroxy-pyrrolidin-1-yl)-ethanone,2-(4-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-N-methylacetamide,tert-butyl4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazine-1-carboxylate,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone,(S)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-(3-hydroxypyrrolidin-1-yl)ethanone,(R)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-(3-hydroxypyrrolidin-1-yl)ethanone,N-(1-(2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)acetoyl)pyrrolidin-3-yl)acetamide,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-(3-fluoroazetidin-1-yl)ethanone,1-(3,3-difluoroazetidin-1-yl)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)ethanone,1-(azetidin-1-yl)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)ethanone,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-(pyrrolidin-1-yl)ethanone,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-morpholinoethanone,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)acetamide,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-(3-(hydroxymethyl)azetidin-1-yl)ethanone,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-N,N-dimethylacetamide,ethyl2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)acetate,ethyl2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)propanoate,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)acetonitrile,N-(6-(4-((1-cyclopropyl-1H-tetrazol-5-yl)methyl)piperazin-1-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,N-(2-ethyl-6-(4-(oxazol-2-ylmethyl)piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,N-(6-(4-((1,2,4-oxadiazol-3-yl)methyl)piperazin-1-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)aceticacid, 2-hydroxyethyl4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazine-1-carboxylate,tert-butyl2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate,tert-butyl3-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate,(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)(pyrrolidin-2-yl)methanone,(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)(pyrrolidin-3-yl)methanone,1-(3-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazine-1-carbonyl)pyrrolidin-1-yl)ethanone,(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)(1-(methylsulfonyl)pyrrolidin-3-yl)methanone,1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-2-hydroxyethanone,1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)propan-1-one,1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-4-hydroxybutan-1-one,4-(dimethylamino)-1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)butan-1-one,N-(2-ethyl-6-(4-(methylsulfonyl)piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,N-(6-(4-(3-chloropropylsulfonyl)piperazin-1-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,N-(6-(4-(3-(dimethylamino)propylsulfonyl)piperazin-1-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,N-(2-ethyl-6-(4-(3-(pyrrolidin-1-yl)propylsulfonyl)piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,3-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-ylsulfonyl)propan-1-ol,methyl2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-ylsulfonyl)acetate,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-ylsulfonyl)aceticacid,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-ylsulfonyl)acetamide,tert-butyl4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-3-oxopiperazine-1-carboxylate,tert-butyl4-(3-((4-(4-chlorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)-3-oxopiperazine-1-carboxylate,ethyl2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-3-oxopiperazin-1-yl)acetate,1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-4-(methylsulfonyl)piperazin-2-one,N-(2-ethyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,N-(6-(1-(chloromethylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,4-(4-chlorophenyl)-N-(2-ethyl-6-(1-(methylsulfonyl)-2,5-dihydro-1H-pyrrol-3-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylthiazol-2-amine,4-(4-chlorophenyl)-N-(2-ethyl-6-(1-(methylsulfonyl)-1,4,5,6-tetrahydropyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylthiazol-2-amine,4-(4-tert-butylphenyl)-N-(2-ethyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylthiazol-2-amine,N-(2-ethyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-methoxyphenyl)-N-methylthiazol-2-amine,N-(2-ethyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-methyl-4-(4-(trifluoromethoxy)phenyl)thiazol-2-amine,4-(3,4-difluorophenyl)-N-(2-ethyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylthiazol-2-amine,3-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-5,6-dihydropyridin-1(2H)-ylsulfonyl)propyl acetate,3-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-5,6-dihydropyridin-1(2H)-ylsulfonyl)propan-1-ol,4-(2-ethyl-3-((4-(4-chlorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-3,6-dihydro-2H-thiopyran1,1-dioxide,N-(2-ethyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)-5-fluoro-4-(4-fluorophenyl)-N-methylthiazol-2-amine,tert-butyl4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-3-hydroxypiperidine-1-carboxylate,4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-1-(methylsulfonyl)piperidin-3-ol,N-(2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,4-(4-tert-butylphenyl)-N-(2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylthiazol-2-amine,N-(2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-methoxyphenyl)-N-methylthiazol-2-amine,4-(3,4-difluorophenyl)-N-(2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylthiazol-2-amine,N-(2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-methyl-4-(4-(trifluoromethyl)phenyl)thiazol-2-amine,N-(2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-methyl-4-(4-(trifluoromethoxy)phenyl)thiazol-2-amine,N-(6-(1-(3-chloropropylsulfonyl)piperidin-4-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,N-(6-(1-(3-(dimethylamino)propylsulfonyl)piperidin-4-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,N-(2-ethyl-6-(1-(3-morpholinopropylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,N-(2-ethyl-6-(1-(3-(pyrrolidin-1-yl)propylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,N-(6-(1-(3-aminopropylsulfonyl)piperidin-4-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,N-(2-ethyl-6-(1-(2-morpholinoethylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidine-1-sulfonamide,3-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-ylsulfonyl)propylacetate,3-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-ylsulfonyl)propan-1-ol,3-(4-(2-ethyl-3-((5-fluoro-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-ylsulfonyl)propan-1-ol,2-(2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorobenzonitrile,2-(2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-5-methylthiazol-4-yl)-5-fluorobenzonitrile,N-(2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluoro-2-methylphenyl)-N-methylthiazol-2-amine,4-(2-chloro-4-fluorophenyl)-N-(2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylthiazol-2-amine,4-(2,4-difluorophenyl)-N-(2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylthiazol-2-amine,N-(2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N,5-dimethylthiazol-2-amine,4-(4-fluorophenyl)-N-(2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(d3-methyl)thiazol-2-amine,4-(4-fluorophenyl)-N-(2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-(d3-methyl)-(d-thiazol-2)-amine,methyl2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carboxylate,1-(2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazol-5-yl)ethanone,N-(2-(2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorophenyl)acetamide,(2-(2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorophenyl)methanol,ethyl2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-5,6-dihydropyridin-1(2H)-yl)acetate,ethyl2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)acetate,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone,(R)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-1-(3-hydroxypyrrolidin-1-yl)ethanone,(S)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-1-(3-hydroxypyrrolidin-1-yl)ethanone,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-1-(3-(hydroxymethyl)azetidin-1-yl)ethanone,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-N,N-dimethylacetamide,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-1-(pyrrolidin-1-yl)ethanone,(S)-1-(2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)acetoyl)pyrrolidine-3-carbonitrile,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-1-(3-(hydroxymethyl)pyrrolidin-1-yl)ethanone,4-((4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)methyl)-1,3-dioxolan-2-one,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-N-(2-hydroxyethyl)-N-methylacetamide,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-N-methoxy-N-methylacetamide,N-(cyanomethyl)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-N-methylacetamide,5-((4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)methyl)oxazolidin-2-one,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-N-(3-hydroxypropyl)acetamide,1-(3,3-difluoroazetidin-1-yl)-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)ethanone,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)acetamide,1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-2-(pyrrolidin-1-yl)ethanone,1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-2-(methylamino)ethanone,1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-2-(3-hydroxyazetidin-1-yl)ethanone,2-(dimethylamino)-1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)ethanone,3-(dimethylamino)-1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)propan-1-one,2-(3,3-difluoroazetidin-1-yl)-1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)ethanone,1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-3-(methylamino)propan-1-one,1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-2-(3-fluoroazetidin-1-yl)ethanone,1-(3-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)azetidin-1-yl)ethanone,5-bromo-N-(2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carboxamide,2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,2-((2-ethyl-6-(4-(2-(3-(hydroxymethyl)azetidin-1-yl)-2-oxoethyl)piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,2-(4-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-N,N-dimethylacetamide,2-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,(R)-2-((2-ethyl-6-(1-(2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,(S)-2-((2-ethyl-6-(1-(2-(3-hydroxypyrrolidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,2-((2-ethyl-6-(1-(2-(3-(hydroxymethyl)azetidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazole-5-carbonitrile,2-(4-(3-((5-cyano-4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-N,N-dimethylacetamide,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-1-(3-(hydroxymethyl)azetidin-1-yl)ethanone,(2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazol-5-yl)methanol,(2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-(trifluoromethoxy)phenyl)thiazol-5-yl)methanol,(2-((6-(1-(3-(dimethylamino)propylsulfonyl)piperidin-4-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazol-5-yl),(2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-(trifluoromethyl)phenyl)thiazol-5-yl)methanol,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-1-(pyrrolidin-1-yl)ethanone,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-1-(3-(hydroxymethyl)azetidin-1-yl)ethanone,2-(dimethylamino)-1-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)ethanone,1-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)propan-1-one,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-N,N-dimethylacetamide,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-N,N-dimethylacetamide,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)-5-(2,2,2-trifluoroacetoyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-N,N-dimethylacetamide,1-(2-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazol-5-yl)-2,2,2-trifluoroethanone,1-(2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazol-5-yl)-2,2,2-trifluoroethanone,2-(2-((2-ethyl-6-(piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-5-methylthiazol-4-yl)-5-fluorobenzonitrile,2-(2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-5-methylthiazol-4-yl)-5-fluorobenzonitrile,2-(4-(3-((4-(2-cyano-4-fluorophenyl)-5-methylthiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-N-methylacetamide,2-(2-((2-ethyl-6-(4-(2-(3-fluoroazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorobenzonitrile,2-(2-((6-(4-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorobenzonitrile,2-(2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorobenzonitrile,2-(2-((6-(4-(2-(azetidin-1-yl)-2-oxoethyl)piperazin-1-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorobenzonitrile,2-(4-(3-((4-(2-cyano-4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-N,N-dimethylacetamide,2-(4-(3-((4-(2-cyano-4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-N-methylacetamide,2-(2-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorobenzonitrile,2-(4-(3-((4-(2-cyano-4-fluorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-N,N-dimethylacetamide,2-(2-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-5-methylthiazol-4-yl)-5-fluorobenzonitrile,2-(5-((2-ethyl-6-(1-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-1,2,4-thiadiazol-3-yl)-5-fluorobenzonitrile,2-(4-(2-(2-cyanoethyl)-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-N,N-dimethylacetamide,3-(3-((4-(4-fluorophenyl)-5-(hydroxymethyl)thiazol-2-yl)(methyl)amino)-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-2-yl)propanenitrile,3-(6-(1-(2-(dimethylamino)-2-oxoethyl)piperidin-4-yl)-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-2-yl)propanamide,N-(6-(3-aminoazetidin-1-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,2-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)azetidin-3-ylamino)-1-(3-hydroxyazetidin-1-yl)ethanone,N-(1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)azetidin-3-yl)-2-(3-hydroxyazetidin-1-yl)acetamide,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)ethanol,N-(2-ethyl-6-morpholinoimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-thiomorpholine1,1-dioxide,1-(3-((4-(4-chlorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)imidazolidin-2-one,ethyl2-(3-(3-((4-(4-chlorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)-2-oxoimidazolidin-1-yl)acetate,4-(4-chlorophenyl)-N-methyl-N-(6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridin-3-yl)thiazol-2-amine,2-(2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)-4-(4-fluorophenyl)thiazol-5-yl)acetonitrile,2-ethyl-N-(4-(4-fluorophenyl)pyrimidin-2-yl)-N-methyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-amine,3-(4-chlorophenyl)-N-(2-ethyl-6-(4-(methylsulfonyl)piperazin-1-yl)imidazo[1,2-a]pyridin-3-yl)-N-methyl-1,2,4-thiadiazol-5-amine,N-(2-ethyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)-3-(4-fluorophenyl)-N-methyl-1,2,4-oxadiazol-5-amine,2-(4-(2-ethyl-3-((3-(4-fluorophenyl)-1,2,4-thiadiazol-5-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-5,6-dihydropyridin-1(2H)-yl)-N,N-dimethylacetamide,2-(4-(2-ethyl-3-((3-(4-fluorophenyl)-1,2,4-thiadiazol-5-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-N,N-dimethylacetamide,N-(6-(4-((1H-imidazol-5-yl)methyl)piperazin-1-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,N-(2-ethyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-methyl-4-(4-(trifluoromethyl)phenyl)thiazol-2-amine,N-cyclopropyl-2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)acetamide,5-((4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)methyl)-3-methyloxazolidin-2-one,(R)-5-((4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)methyl)oxazolidin-2-one,(S)-5-((4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)methyl)oxazolidin-2-one,4-((4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)methyl)oxazolidin-2-one,N-(2-ethyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)-3-(4-fluorophenyl)-N-methyl-1,2,4-thiadiazol-5-amine,1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)propane-1,2-dione,5-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazine-1-carbonyl)pyrrolidin-2-one,(1-aminocyclopropyl)(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)methanone,(S)-1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-2-hydroxypropan-1-one,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-2-oxoacetamide,1-benzyl-4-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazine-1-carbonyl)pyrrolidin-2-one,3-(3-((4-(4-chlorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)oxazolidin-2-one,2-(2-ethyl-3-((4-(4-chlorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-1-[1,2]thiazinane-1,1-dioxide,4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-N-(thiophen-2-yl)-5,6-dihydropyridine-1(2H)-carboxamide,4-(4-chlorophenyl)-N-(2-ethyl-6-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylthiazol-2-amine,4-(4-chlorophenyl)-N-(2-ethyl-6-(1-(trifluoromethylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylthiazol-2-amine,1-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-4-ol,2-(4-(3-((4-(4-chlorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)ethanol,4-(2-ethyl-3-((4-(4-chlorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-thiomorpholine-1,1-dioxide,tert-butyl4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate,1-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)propan-1-one,N-(2-ethyl-6-(piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,N-(6-(1-benzylpiperidin-4-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,N-(2-ethyl-6-(1-isopropylpiperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,tert-butyl4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidine-1-carboxylate,N-(6-(3,6-dihydro-2H-pyran-4-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,4-(4-chlorophenyl)-N-(6-(3,6-dihydro-2H-pyran-4-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-N-methylthiazol-2-amine,(2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-4,5-dihydrooxazol-5-yl)methanol,2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidin-1-yl)-1-(3-hydroxypyrrolidin-1-yl)ethanone,2-(2-((2-ethyl-6-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)(methyl)amino)thiazol-4-yl)-5-fluorophenol,tert-butyl4-(3-((3-(4-chlorophenyl)-1,2,4-thiadiazol-5-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)piperazine-1-carboxylate,N-(6-(4-((1H-imidazol-2-yl)methyl)piperazin-1-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,cyclopropyl(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)methanone,ethyl2-(4-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperazin-1-yl)-2-oxoacetate,[6-(1,1-Dioxo-isothiazolidin-2-yl)-2-ethyl-imidazo[1,2-a]pyridin-3-yl]-[4-(4-fluoro-phenyl)-thiazol-2-yl]-methyl-amine,tert-butyl4-(3-((4-(4-chlorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate,4-(4-chlorophenyl)-N-(6-(3,6-dihydro-2H-thiopyran-4-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-N-methylthiazol-2-amine,N-(6-(4,4-difluoropiperidin-1-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,N-(6-(1-(3-chloropropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,tert-butyl4-(3-((4-(4-chlorophenyl)thiazol-2-yl)(methyl)amino)-2-ethylimidazo[1,2-a]pyridin-6-yl)piperazine-1-carboxylate,N-(6-(1-(cyclohexylmethyl)piperidin-4-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,N-(2-ethyl-6-(5-methyl-4,5-dihydrooxazol-2-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,N-(2-ethyl-6-(4-methyl-4,5-dihydrooxazol-2-yl)imidazo[1,2-a]pyridin-3-yl)-4-(4-fluorophenyl)-N-methylthiazol-2-amine,2-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-4,5-dihydrooxazole-4-carboxylicacid,(2-(2-ethyl-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)-4,5-dihydrooxazol-4-yl)methanol,and4-(4-chlorophenyl)-N-(6-(4,5-dihydrooxazol-2-yl)-2-ethylimidazo[1,2-a]pyridin-3-yl)-N-methylthiazol-2-amine.15) A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a pharmaceutically effective amount of a compoundor pharmaceutically acceptable salt thereof according to claim
 1. 16) Apharmaceutical composition according to claim 15, comprising a furthertherapeutic agent. 17) A method of inhibiting ectonucleotidepyrophosphatase/phosphodiesterase 2 (ENPP2), which method comprisescontacting the ENPP2 with a compound or pharmaceutically acceptable saltthereof according to claim
 1. 18) A method of treating fibroticdiseases, proliferative diseases, inflammatory diseases, autoimmunediseases, respiratory diseases, cardiovascular diseases,neurodegenerative diseases, dermatological disorders, and/or abnormalangiogenesis associated diseases, which method comprising administeringto a subject in need thereof a compound or pharmaceutically acceptablesalt thereof, according to claim
 1. 19) A method according to claim 18,wherein the compound or pharmaceutically acceptable salt thereof isadministered in combination with a further therapeutic agent. 20) Themethod according to claim 19, wherein the further therapeutic agent isfor the treatment of fibrotic diseases, proliferative diseases,inflammatory diseases, autoimmune diseases, respiratory diseases,cardiovascular diseases, neurodegenerative diseases, dermatologicaldisorders, and/or abnormal angiogenesis associated diseases.